bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 100: Mas Receptor Expression in Bone Marrow Stem/Progenitor Cells is Both Required and Sufficient for the Mobilization of Cells in Response to Ischemic Injury
Authors: Joshi Shrinidh , Vasam Goutham , Adkins Steven , Thatcher Sean E , Bradley David S , Cassis Lisa A , Jarajapu Yagna P
Published: September 2019

Bone marrow-derived hematopoietic stem/progenitor cells (HSPCs) are mobilized into the circulation in response to ischemic injury and stimulate vascular regeneration. Angiotensin-(1-7) (Ang-(1-7)) activates vasoprotective functions in progenitor cells by activating Mas receptor (MasR). We have shown that mobilization of progenitor cells in response to ischemic injury is impaired in MasR
-/-
mice (KO) and that blood flow recovery is reduced. This study tested if MasR expression in the bone marrow-resident HSPCs is sufficient to rescue mobilization in MasR
-/-
mice. Bone marrow chimeric mice were made by lethal irradiation of wild type (WT) or MasR
-/-
mice followed by transplantation with bone marrow derived from either WT or KO mice. Circulating lineage-negative Sca-1
+
and cKit
+
(LSK) cells were enumerated in basal or in response to the treatment with plerixafor (5 mg/Kg, ip) or G-CSF (125 mg/Kg, sc, twice-a-day, four days). Hind-limb ischemia (HLI) was induced by femoral artery ligation and the circulating LSK cells were monitored over time. Either WT or MasR
-/-
mice transplanted with MasR
-/-
bone marrow have shown 100% mortality following irradiation (n=6). Circulating LSK cells are lower in MasR
-/-
mice (14±5 cells/mL of blood) compared to WT (39±7/mL, P<0.01, n=6). On the other hand, circulating cells were comparable in WT→MasR
-/-
(20±3/mL blood) and WT→WT chimeras (31±6/mL, n=6). Mobilization of LSK cells by plerixafor (5 mg/Kg, ip) or G-CSF (125 mg/Kg, sc., twice-a-day, four days) are lower in MasR
-/-
mice (4- and 2-fold, respectively, compared to WT, P<0.05, n=6). In contrast, WT→MasR
-/-
or WT→WT chimeras responded similarly to either of the mobilizers, and responses were comparable to that observed in WT mice. Mobilization of LSK cells in response to HLI is attenuated to a maximum of 5-fold on day-5 post-HLI in MasR
-/-
mice (vs 10-fold in WT on day-3 post-HLI, P<0.05 n=5). This response was rescued to a larger extent in WT→MasR
-/-
chimeras (7-fold, compared to 9-fold in WT→WT chimeras, P<0.05, n=5). These studies infer that MasR
-/-
HSPCs cannot rescue WT or MasR
-/-
mice following lethal irradiation, and that MasR expression in the bone marrow HSPCs is sufficient and required for mobilization of cells in response to mobilizers or to an ischemic injury.
Abstract 101: Novel AT2 Receptor Agonists are Cardio- and Reno-Protective
In Vitro
and
In Vivo
Authors: Wang Yan , Del Borgo Mark , Aguilar Mibel , Samuel Chrishan , Widdop Robert
Published: September 2019

Targeting the angiotensin type 2 receptor (AT
2
R) evokes anti-fibrotic effects in various organs. A single β-amino acid substitution for proline in angiotensin III (β-Pro
7
-Ang III) markedly improved the AT
2
R:AT
1
R selectivity over 20,000-fold. Additionally, tryptophan substitution in position 8 (β-Pro
7
-Trp
8
-Ang III) further improved the AT
2
R:AT
1
R selectivity, while a D-arginine substitution (D-Arg
2
- β-Pro
7
-Trp
8
-Ang III) or N-Acetyl attachment (N-Ac-β-Pro
7
-Trp
8
-Ang III) increased in vitro plasma stability. The aim of this study was to determine the anti-fibrotic effects of these novel AT
2
R selective ligands (β-Pro
7
-Trp
8
-Ang III; D-Arg
2
-β-Pro
7
-Trp
8
-Ang III; N-Ac-β-Pro
7
-Trp
8
-Ang III) in vitro and in high salt (HS) diet-induced heart and kidney disease. Human cardiac fibroblasts (HCFs) were treated with TGF-β1 in the absence or presence of ligands for 72 hours. Collagen levels in HCFs were measured by Western blot analysis. Male FVB/N mice were subjected to 8 weeks of HS (5%)-induced cardiac and renal fibrosis. From weeks 5-8, sub-groups of mice (n=8-9/group) were treated with either β-Pro
7
-Trp
8
-Ang III, D-Arg
2
-β-Pro
7
-Trp
8
-Ang III or N-Ac-β-Pro
7
-Trp
8
-Ang III (all 0.1 mg/kg/day) via subcutaneous mini-pumps. Various markers of cardiac and renal inflammation, fibrosis, and collagen turnover were measured. All peptides markedly reduced TGF-β1-induced collagen I production in HCFs (all P<0.05 vs. TGF-β1). Compared with normal salt (NS), HS increased cardiac collagen by hydroxyproline (from 1.5 ± 0.05 to 2.2±0.08 % collagen/dry tissue weight) and picrosirius red (from 4.8±0.36% to 6.9±0.59% of area) analyses (both P<0.05). Each peptide reversed fibrosis (all P<0.05 vs HS; both methods) and similar anti-fibrotic effects of all peptides occurred in kidneys. These effects were associated with reduced myofibroblast differentiation (α-SMA) in heart and kidney (all P<0.05 vs HS). Moreover, HS-induced cardiac and renal inflammation (p-IκB and F4/80 immunofluorescence) were increased by 50%-80% (from NS of 1.5-2% area); all indices were reversed by each peptide (all P<0.05). In conclusion, highly AT
2
R-selective ligands were cardio- and reno- protective, highlighting the therapeutic strategy of AT
2
R stimulation to treat organ fibrosis.
Abstract 107: Bradykinin B
2
Receptor Blockade Prevents Excessive Blood Pressure Reduction During Hemodialysis
Authors: Gamboa Jorge L , Falck Aaron , Mambungu Cindy , Clagett Adrienne , Ikizler T. Alp , Brown Nancy J
Published: September 2019

Intradialytic hypotension (IDH) is a common clinical complication of hemodialysis in patients with end-stage renal disease and it is associated with increased morbidity and mortality. The pathogenesis of IDH has been attributed to a rapid removal of plasma volume during hemodialysis and the inadequate compensatory mechanisms to hypovolemia, such as the lack of vasoconstriction. This may be due to the removal of vasoconstrictors or the increased production of vasodilators, such as bradykinin. Thus, we tested the hypothesis that bradykinin B
2
receptor blockade prevents intradialytic hypotension. For this purpose, we conducted a double-blind, placebo controlled, randomized, 2x2 crossover clinical trial comparing the continuous infusion of icatibant, a bradykinin B
2
receptor blocker, and placebo during hemodialysis. We evaluated 11 patients who underwent adequate hemodialysis thrice weekly for at least 6 consecutive months. Icatibant or placebo were infused for 30 minutes before and during hemodialysis. Seven of the patients have IDH, defined as a reduction of systolic blood pressure equal or greater than 20 mmHg during hemodialysis. Stratified analysis, based on the presence of IDH, revealed that icatibant prevents the decrease in blood pressure compared to placebo in patients with IDH (change in blood pressure from baseline: Placebo -13.0±9.8
vs
. icatibant 1.8±18.8 mmHg, mean±S.D,
Figure 1
). Icatibant has no effect on blood pressure in the group of patients without IDH. Further studies should evaluate not only the hemodynamics effect of icatibant during hemodialysis, but also its efficacy on preventing the symptomatology associated with IDH.
Abstract 112: Soluble (pro) Renin Receptor Serves as Novel Insulin Sensitizing Agent in Mice With Diet-Induced Obesity
Authors: Wang Fei , Luo Renfei , Zou Chang-Jiang , Xie Shiying , Peng Kexin , Zhao Long , Yang Kevin T , Xu Chuanming , Yang Tianxin
Published: September 2019

Thiazolidinediones, the PPARgamma agonists, represent a unique class of insulin sensitizers for management of hyperglycemia in type 2 diabetes but are limited by the side effect of fluid retention. Here we report therapeutic potential of histidine-tagged recombinant soluble (pro)renin receptor (sPRR), termed as sPRR-His, in a mouse obesity model induced by 9-month high fat diet (DIO) for management of glucose dysregulation. In the DIO mice, a 2-wk administration of sPRR-His lowered body weight (47.0 ± 1.4 vs. 52.8 ± 1.2 g) and remarkably improved multiple metabolic parameters including hyperglycemia (serum glucose: 148.8 ± 19.1 vs. 224.8 ± 12.5 mg/dL), hyperinsulinemia (serum insulin: 3.7 ± 0.4 vs. 10.9 ± 0.9 ng/ml), glucose intolerance, albuminuria (urine albumin/ Creatinine: 63.4 ± 3.5 vs. 97.7 ± 10.2 mg/g), and glomerular hyperfiltration (GFR: 264.7 ± 12.2 vs. 521.3 ± 18.2 μl/min) in the absence of fluid retention (plasma volume: 28.7 ± 1.2 vs. 27.8 ± 0.9 μl/g). GFR and plasma volume were measured by using FITC-sinistrin (7.5mg/100g i.v.) and FITC-dextran (2 mg/100 g i.v.) respectively. Conversely, inhibition of endogenous sPRR production by PF429242, an inhibitor of site-1 protease induced diabetes and insulin resistance which were reversed by sPRR-His supplement. At cellular level, sPRR-His enhanced insulin-induced increases in glucose uptake via upregulation of phosphorylated AKT and protein abundance of Glut4. Promoter and gene expression analysis revealed PRR as a direct target gene of PPARγ. Adipocyte-specific PPARγ deletion induced severe diabetes (blood glucose: 243.6 ± 39.8 vs. 108.4 ± 2.1 mg/dL) and insulin resistance (plasma insulin: 48.9 ± 4 vs. 1.5 ± 0.2 ng/ml) associated with reduced adipose PRR expression and circulating sPRR (plasma sPRR: 265.7 ± 14 vs. 893.0 ± 86.8 pg/ml). sPRR-His supplement in the null mice nearly normalized blood glucose (142.4 ± 12.2 mg/dL) and insulin level (14.3 ± 7.9 ng/ml). Additionally, sPRR-His treatment suppressed DIO-induced renal sodium-glucose cotransporter-2 (SGLT2) expression. Overall, sPRR-His exerts potent hypoglycemic action via serving as a mediator of insulin-sensitizing action of thiazolidinedione as well as a negative regulator of renal SGLT2 in the absence of fluid retention side effect.
Abstract 113: Chemerin Regulates Adipocyte Size in Mesenteric Perivascular Adipose Tissue When on a Normal but Not High Fat Isocaloric Diet
Authors: Ferland David J , Garver Hannah , Contreras Andres G , Fink Gregory D , Watts Stephanie W
Published: September 2019

Chemerin is an adipokine, positively associated with blood pressure, and used as a marker for metabolic syndrome. We hypothesized that a global knockout (KO) of chemerin in the rat would lead to a global decrease in white visceral fat mass in both control (C) and high-fat (HF) diets. Wild-type (WT) and KO rats on a Sprague-Dawley background were fed a C (10% kcal fat) or HF (60% kcal fat) diet with weekly monitoring of body weight and food consumption. MicroCT was performed at 8 weeks and 25 weeks of age to measure subcutaneous and intrabdominal fat. Blood pressure was measured by radiotelemetry measuring for 10 seconds every 10 minutes for 24 hours/day. At the end of 25 weeks, fats were dissected and flash frozen for PCR analysis or fixed with paraformaldehyde for histology. There were no physiologically relevant differences in blood pressure (table). Within each diet, there were no significant differences in final total body weight (table). KO-C had reduced intrabdominal fat when compared to WT-C. Histology of the KO-C intrabdominal white fat components revealed a significant leftward shift in mesenteric adipocyte area compared to WT-C (table; p = 0.01 by the Kolmogorov-Smirnov test) but no changes in retroperitoneal adipocytes. RNA expression of perilipin, adiponectin, and fatty acid synthase normalized to beta-2 microglobulin were all undetectable only in the mesenteric fat, not retroperitoneal fat, of KO-C animals compared to WT-C (table). These data are the first to provide
in vivo
support for the role of chemerin in adipogenesis but also indicates that chemerin’s role in adipocyte development specific to a location vital for blood pressure regulation.
Abstract 114: Renal Inflammation Correlates With Pararenal and Perirenal Adipose Inflammation in Obesity
Authors: Jelinic Maria , Tran Vivian , Diep Henry , Sobey Christopher G , Drummond Grant R , Vinh Antony
Published: September 2019

The global obesity epidemic has led to a 10-fold increase in the incidence of obesity-related chronic kidney disease, highlighting the need for improved understanding of its pathogenesis. Perirenal and pararenal fat capsules surround the kidneys and the thickness of these specific fat deposits is an independent predictor of chronic kidney disease in type-2 diabetes patients. Whilst visceral fat is well-known to promote inflammation in obesity, the role of pararenal and perirenal fat in renal inflammation is still unknown. Due to their close proximity to the kidneys, we hypothesize that pararenal and perirenal fat deposits directly cause renal inflammation and damage in obesity. Thus, we aimed to characterize perirenal, pararenal and renal inflammation in a diet-induced mouse model of obesity. Six-week-old male C57BL/6 mice were fed either normal chow (NC; n=12) or a high-fat diet (HFD; n=12) for 10 weeks. Compared with NC, the HFD resulted in greater bodyweight (38.4±1.1g vs. 29.4±0.6g), blood cholesterol (184±13mg/dL vs. 115±6mg/dL) and fasting blood glucose levels (12.3±0.6mmol/L vs. 9.7±0.3mmol/L) by the completion of the diet regimen (all
P
<0.05). Flow cytometry was used to enumerate immune cell populations in the blood, kidneys and surrounding (perirenal and pararenal) adipose. In HFD mice, the frequency of CD11b+ cells and inflammatory (Ly6CHi) monocytes was higher in the blood (34±2% vs. 26±2% and 15±1% vs. 8±1%), perirenal (37±5% vs. 19±5% and 8±1% vs. 4±1%) and pararenal fat (65±4% vs. 50±3% and 8±1% vs. 3±1%) than in NC mice (all
P
<0.05). This was associated with greater Ly6CHi monocyte infiltration in the kidneys from HFD mice (
P
<0.05). Interestingly, renal neutrophils (Ly6G+) were more prevalent in HFD than NC mice (3.5±0.5% vs. 2.2±0.3%;
P
<0.05), but not in pararenal and perirenal adipose. Our data is the first to reveal similarities in the inflammatory cell profiles of blood, perirenal and pararenal adipose tissues and kidneys during obesity.
Abstract 115: Downregulation of Perivascular Adipose Tissue PPAR Gamma in Western Diet-Induced Persistent Vascular Dysfunction in Female Rats
Authors: Carrillo-Sepulveda Maria A , Maddie Nicole , Persand Dhandevi
Published: September 2019

Consumption of a western diet (WD) is a major part of modern life contributing to the epidemic of Metabolic Syndrome (MS), a significant risk factor for cardiovascular disease. Recent studies from our laboratory have characterized a model of WD induced MS in female rats. Adopting a healthier diet may be sufficient to reverse the constellation of metabolic symptoms associated with MS including obesity-related hypertension. However, it remains unclear if returning to a normal diet overcomes cardiovascular dysfunction associated with MS. We hypothesized that cardiovascular dysfunction will persist despite diet reversal due to altered PPAR-γ, an important vascular tone regulator, in the perivascular adipose tissue (PVAT). Eight-week old female Wistar rats were fed a WD (21% fat, 50% carbohydrate (34% sucrose) for 20 weeks (WD group) to induce MS. Then, the rats were subjected to diet reversal for 8 weeks (rWD group). The control group received a regular chow diet (5% fat, 48.7% carbohydrate (3.2% sucrose). WD group exhibited increased body weight, triglyceride levels, intolerance to glucose and systolic blood pressure characterizing MS. Direct measurement of blood pressure via right carotid catheterization showed that WD increased systolic blood pressure (141.61 ± 10 vs. 119.52 ± 9 mmHg) compared with controls. Strikingly, diet reversal was unable to drop systolic blood pressure (139.87 ± 13 mmHg). WD impaired acetylcholine and sodium nitroprusside-mediated relaxation in aortic rings. These effects remained unchanged even after diet reversal. Expression of PPAR-γ in aortic PVAT was significantly reduced in the WD group (3.2 fold) and in the rWD group (2.4 fold ) compared with controls. Moreover, we found high levels of lysine acetylation in the PVAT from WD (2.8 fold ) and rWD group (2.0 fold) compared with controls. Despite reversal WD led to significant improvement of all metabolic parameters, including weight loss, this strategy was unable to reverse vascular dysfunction and elevated blood pressure caused by WD consumption. Decreased PPAR-γ expression in PVAT associated with hyperacetylation will be further examined as a potential mechanism underlying persistent vascular dysfunction in WD-induced MS.
Abstract 121: Leptin Restores Endothelial Function, Diminishes Vascular Adrenergic Contractility, but Does Not Alter Arterial Stiffness and Blood Pressure, in a Mouse Model of Congenital Generalized Lipodystrophy
Authors: Bruder-Nascimento Thiago , L. Faulkner Jessica , Kennard Simone , Antonova Galina , Chen Weiqin , Belin de Chantemele Eric J
Published: September 2019

Leptin which has been associated with cardiovascular disease in the context of obesity, is the current treatment for the metabolic disorders associated with congenital generalized lipodystrophy (CGL). However, the effects of chronic leptin infusion on vascular function and arterial pressure remain unknown in CGL. Here, we hypothesized that deletion in leptin will alter while leptin infusion will restore cardiovascular function via direct vascular mechanisms in CGL in male Berardinelli-Seip 2 gene deficient mice (gBscl2-/-), a mouse model of CGL. CGL mice exhibited reduced adipose mass and leptin levels (gBscl2+/+: 4.03 ± 0.3 vs gBscl2-/-: 0.38 ± 0.1*, ng/dL *P<0.05), as well as evidence of cardiovascular dysfunction including impaired endothelium-dependent relaxation, increased vascular contractility for phenylephrine (gBscl2+/+: 55.3 ± 1 vs gBscl2-/-: 106.2 ± 2.7*, Emax *P<0.05), augmented pulse wave velocity (PWV) (gBscl2+/+: 259.6 ± 20.4 vs gBscl2-/-: 412.4 ± 2.7*, cm/s *P<0.05), vascular fibrosis and elevated mean arterial pressure (MAP) (gBscl2+/+: 100.7 ± 1.4 vs gBscl2-/-: 109.5 ± 2*, mmHg *P<0.05). Blood vessels from CGL mice exhibit increased Nox1 expression gene expression (3 fold) and reactive oxygen species production. Nox1 inhibition (GKT771 10
-5
M) or PPARγ activator (Pioglitazone 10
-5
M) restored endothelial function. Remarkably, chronic (0.3mg/day/7 days) and acute leptin supplementation restored endothelial function and decreased Nox1 expression and ROS production. Selective genetic ablation of leptin receptors in endothelial cells promoted endothelial dysfunction, via Nox-1 dependent mechanisms. Furthermore, leptin reduced vascular adrenergic contractility, but did not reduce MAP, nor PWV or vascular fibrosis in CGL. In conclusion, leptin restores endothelial function via PPARγ-dependent decreases in Nox1, reduces vascular adrenergic contractility, but does not affect the blood pressure and vascular structure, in gBscl2-/- mice. These data reveal a new direct role of leptin receptors in the control of vascular homeostasis and present leptin as a potential therapy for the treatment of vascular disease associated with low leptin levels.
Abstract 122: Cardiac Hypertrophy and Vascular Function are Directly Proportional to Mitochondrial Variations in Intrinsic Exercise Capacity
Authors: Roy Shaunak , Edwards Jonnelle M , Tomcho Jeremy C , Bearss Nicole R , McCarthy Cameron G , Zhang Youjie , Spegele Adam C , Koch Lauren G , Joe Bina , Wenceslau Camilla F
Published: September 2019

Exercise is a primary lifestyle intervention to control cardiovascular diseases such as hypertension. Exercise capacity and its health benefits are inheritable. However, the mechanisms by which exercise capacity differences influence overall health state remain unclear. We first hypothesized that low and high intrinsic exercise capacity lead to distinct heart weight and vascular function. Animal model (male, 20-24-weeks old, n = 6): heterogeneous stock selectively bred for over 20 years to produce low-capacity running rats (LCR) and high-capacity running rats (HCR), and an intrinsic control, high response trainer rats (HRT, control). Statistics: t-test: *p<0.05. Left ventricular (LV) weight was normalized by tibia length. We observed that HCR presented with LV hypertrophy compared to LCR and control (Control: 0.0155 ± 0.0006 vs. HCR: 0.0192 ± 0.0007* vs. LCR: 0.0164 ± 0.0004). Performing wire myography with 3
rd
-order mesenteric resistance arteries (MRA), we observed that LCR MRA had an impaired maximum relaxation response (E
max
) to acetylcholine (ACh) compared to HCR and control (Control: 94.99 ± 1.79 vs. HCR: 93.49 ± 12.17 vs. LCR: 72.95 ± 12.40*). Next, we questioned if these differences were the result of mitochondria. We used two reciprocal conplastic strains created by utilizing maternal mitochondrial inheritance (male, 30-36-weeks old, n = 4): LCR nuclear genome with HCR mitochondria (LCR.HCR
mt
) and the reciprocal HCR.LCR
mt
. We observed that LCR.HCR
mt
presented with LV hypertrophy compared to LCR (0.0195 ± 0.0002* vs 0.0164 ± 0.0004) while HCR.LCR
mt
abolished HCR LV hypertrophy (0.0151 ± 0.0002* vs. 0.0192 ± 0.0007). Interestingly, in a separate group of animals (n = 4 - 5), LCR had higher mean arterial pressure (MAP) compared to HCR, and LCR.HCR
mt
had reduced MAP compared to LCR (LCR: 119 ± 2 vs. LCR.HCR
mt
: 111 ± 1*). No changes were observed in HCR.LCR
mt
compared to HCR. Further, LCR.HCR
mt
MRA presented with improved E
max
to ACh compared to LCR MRA (LCR: 72 ± 12 vs. LCR.HCR
mt
: 93 ± 2*) while no changes were observed in HCR.LCR
mt
MRA compared to HCR MRA. Overall, we conclude that intrinsic exercise capacity is directly proportional to cardiovascular effects. Similar to the nuclear genome, mitochondria are the key to this hereditary predisposition.
Abstract 125: Low-Grade Chronic Infection Induces Vascular Dysfunction and Remodeling in Salt Sensitive Hypertension
Authors: Edwards Jonnelle , Galla Sarah , Tomcho Jeremy C , McCarthy Cameron G , Bearss Nicole , Roy Shaunak , Mell Blair , Cheng Xi , Joe Bina , Wenceslau Camilla F
Published: September 2019

According to the new AHA guidelines, over half of Americans have hypertension. Multiple factors contribute to hypertension including genetics, diet, stress, and infection. N-formyl peptides (NFPs) are a potent chemoattractant that bind formyl peptide receptors (FPR), an innate immune receptor. Interestingly, the only source of NFPs are bacteria and mitochondria, which evolved from bacteria. We have observed that FPR is expressed in arteries and its activation with bacterial (fMLPs) or mitochondrial (FMIT) NFPs induces vascular remodeling via actin polymerization. Given that increased gut permeability is present in hypertension, we questioned if bacterial NFPs derived from a leaky gut also play a role in hypertension. We hypothesized that bacterial NFPs activate FPR leading to vascular dysfunction and remodeling. We used male (6 weeks) Dahl Resistant (DR) and Sensitive (DS) rats on a low (0.3 %) or high salt (2 %) diet for 9 weeks. After 6 weeks some animals on high salt received water + antibiotic [neomycin (NEO), 0.5 g/L or amoxicillin (AMO), 50 mg/kg/day) for 3 weeks to decrease bacterial levels. Statistics: t-test *p<0.05. We observed that FPR mRNA expression was increased in aorta from DS (low-salt) when compared to DR (low-salt) (DR: 0.96 ± 0.7 vs. DS: 1.3 ± 1.7*), suggesting that FPR is activated prior to the onset of hypertension. High-salt diet increased FPR mRNA expression in aorta from DR, but did not exacerbate it in DS compared to DS (low-salt). Phenylephrine and acetylcholine concentration-response curves (1nM – 1μM) were performed in mesenteric resistance arteries using wire myography. Due to increased arterial stiffness from severe hypertension in DS (high salt), these rats showed a decrease in contraction compared to DR. DS treated with NEO or AMO ameliorated this response (tension (mN): Emax: DS 11 ± 4 vs. DS+ NEO 17 ± 2*, S + AMO 17 ± 0.9*). No changes were observed in the relaxation curve. Using pressure myograph, it was observed that NEO and AMO reverted vascular remodeling [wall thickness (μm): DS 55 ± 4 vs. DS + NEO 38 ± 9* and DS + AMO 31± 9*; cross sectional area (μm
2
): DS 45,624 ± 1370 vs. DS + NEO 28,700 ± 8370* and DS + AMO 23,276 ± 9775*]. We concluded that low-grade chronic infection plays a role in vascular dysfunction and remodeling observed in hypertension.
Abstract 127: The Lung-Associated Self-Antigen Type V Collagen is Regulated by Nuclear Factor of Activated T Cells Isoform c3 in Chronic Hypoxia
Authors: Jones David T , Lantz Benjamin J , Guo Yan , Jankowska-Gan Ewa , Burlingham William J , Gonzalez Bosc Laura V
Published: September 2019

Chronic hypoxia (CH)-induced pulmonary hypertension (PH) is a progressive and often fatal consequence of chronic lung diseases, chronic exposure to high altitude and sleep apnea. PH results from arterial remodeling, enhanced vasoreactivity, and Th17 cell-mediated perivascular inflammation. Naturally occurring “nTH17” cells, can be detected in fetal life and are in homeostatic equilibrium with natural T regulatory cells. nTH17 cells are specific for a limited range of self-antigens, including type V collagen (colV). ColV is normally hidden from the immune system within type I col in the extracellular matrix of the lungs. We have shown that type V collagen is a self-antigen uncovered by CH. On the other hand, we have shown that mice lacking nuclear factor of activated T cells isoform c3 (NFATc3) globally and specifically in smooth muscle (SMC-NFATc3 KO) are protected from CH-induced PH. No differences in cardiac function were detected between SMC-NFATc3 KO and control mice using a Vevo LAZR-X ultrasound system before CH.
In silico
analysis of Col5A1 promoter shows NFATc3 binding sites. Therefore, we hypothesized that smooth muscle NFATc3 upregulates Col5A1 expression contributing to the development of acute autoreactivity to collagen V in response to CH, representing an upstream mechanism in PH development.

Col5A1 was one of the 1792 genes differentially affected by both CH and smooth muscle NFATc3 in isolated pulmonary arteries (RNA Illumina Sequencing). Col5A1 mRNA increased significantly after 5 days of CH in control mice (fold change from normoxia±SD=2.2±0.8, n=5) vs. SMC-NFATc3 KO (0.8±0.3, n=3, p<0.03). Cellular autoimmunity to colV was determined using a trans-vivo delayed-type hypersensitivity assay (TV-DTH). Splenocytes from 5 days CH-exposed control mice displayed a TV-DTH colV response significantly higher than that from CH-exposed SMC-NFATc3 KO mice (footpad swelling [10
-4
”] ± SD of naïve recipient mice injected with cells from CH control mice 25.6±4.2, n=8 vs. CH SMC-NFATc3 KO mice 5.3±0.5, n=7; p<0.0001).

Our results suggest that smooth muscle NFATc3 is important for CH-induced PH in adult mice, in part, by regulating the expression of the lung self-antigen ColV contributing to pulmonary vascular inflammation.
Abstract 130: Down Regulation of Gamma-Adducin Diminishes Glomerular Function and Promotes Hypertension Related Chronic Kidney Disease
Authors: He Xiaochen , Wang Shaoxun , Guo Ya , Gao Wenjun , Roman Richard J , Fan Fan
Published: September 2019

Fawn Hooded Hypertensive (FHH) rats are a genetic model of hypertension-induced chronic kidney disease (CKD) in association with podocyte dysfunction. We previously identified an inactivating mutation of γ-Adducin (ADD3) is associated with the development of proteinuria in FHH rats and that knockdown of ADD3 disrupts actin cytoskeleton structure in the vascular smooth muscle cells. However, whether loss of ADD3 function also alters podocyte function in FHH rats has not been studied. The present study examined whether loss of ADD3 function in FHH also alters the actin cytoskeleton and podocyte function and contribute to the development of CKD. Knockdown of Add3 in the conditionally immortalized mouse podocytes using Add3 DsiRNA disrupted the actin cytoskeleton and increased F/G actin ratio using immunostaining and Western blots. Mean arterial pressure was similar, but proteinuria increased to a lesser extent in the DOCA/salt hypertensive FHH.Add3 transgenic (259 ± 5 mg/day, n=12) than FHH (484 ± 78 mg/day, n=21) rats. The convective permeability of isolated glomeruli to albumin (Palb) was lower in FHH.Add3 (0.13 ± 0.01, n=6, 157) than FHH (0.24 ± 0.02, n=4, 173) rats as assessed by a fluorescence dilution technique. Moreover, Palb increased to greater extent in FHH (0.36 ± 0.03, n=5, 140) than in FHH.Add3 (0.21 ± 0.03, n=3, 75) rats after DOCA/salt hypertension. Hypertensive FHH.Add3 rats exhibited less podocyte foot process effacement than FHH rats. The glomerular injury score averaged 2.50 ± 0.03 (n=9, 270) in DOCA/salt hypertensive FHH.Add3 versus 3.31 ± 0.01 (n=9, 270) in FHH rats. The percentage of fibrosis in the renal cortex was significantly lower in hypertensive FHH.Add3 than age-matched FHH rats. These results indicate that loss of ADD3 function contributes to the development of proteinuria and CKD in FHH rats by altering the actin cytoskeleton in podocytes, leading to podocyte effacement and glomerular barrier dysfunction.
Abstract 133: The Role of Xanthine Dehydrogenase (
XDH
) and Uric Acid in Renal Damage
Authors: Dissanayake Lashodya , Spires Denisha , Levchenko Vladislav , Palygin Oleg , Staruschenko Alexander
Published: September 2019

Uric acid is the end product of purine catabolism in humans and is capable of acting as both an antioxidant scavenging reactive oxygen species and conditionally a pro-oxidant. Increased or decreased serum uric acid level (hyperuricemia or hypouricemia, respectively) are associated with a number of prevalent diseases including hypertension and chronic kidney disease as well as with rare disorders, such as primarily hereditary xanthinuria. Despite the clear association of uric acid dysregulation with pathophysiology, the mechanisms involved remain unclear. Xanthine oxidoreductase (XOR), XDH or xanthine oxidase (XO) is a complex metalloflavoenzyme that catalyzes the oxidation of hypoxanthine to xanthine and xanthine to uric acid. To assess the physiological and pathophysiological role of this pathway, we created a genetic ablation of
Xdh
gene in the Dahl salt-sensitive rat background (SS
Xdh-/-
). Genomic DNA sequencing of the SS
Xdh-/-
rat model confirmed a 7-base-pair-deletion in exon 4 of the
Xdh
gene located on chromosome 6. SS
Xdh-/-
rats exhibited early mortality with 75% (21/28 rats) survival probability up to 45 days of age compared to SS
Xdh+/-
and SS
Xdh+/+
littermates, all of whom survived. Plasma uric acid of 6 weeks old male rats was 0.27±0.03 mg/dl (N=3) and in SS
Xdh+/+
rats decreased to a level out of the detectable range by the test in the SS
Xdh-/-
group. The uric acid/creatinine ratio in urine for SS
Xdh+/+
rats was 0.27±0.01 (N=3) and extremely decreased for SS
Xdh-/-
rats (out of the range). In addition, the SS
Xdh-/-
rats showed severe renal damage with interstitial fibrosis and dilated tubules by Masson’s Trichrome staining. Kidney damage was further evident by the increased levels of albumin excretion in the SS
Xdh-/-
rats (1.21±0.28 (N=3) and 2.86±0.91 (N=6) for SS
Xdh+/+
and SS
Xdh-/-
, respectively). The kidney weight / total body weight ratio was increased in SS
Xdh-/-
rats, indicating renal hypertrophy compared to control (10.97±0.2 (N=3) and 15.92±0.81 (N=5) for SS
Xdh+/+
vs SS
Xdh-/-
rats). These results suggest that genetic ablation of
Xdh
caused uric acid depletion and severe renal damage.
Xdh
may be essential for the development of the kidney and survival of the rats by regulating purine catabolism.
Abstract 138: Acute Stimulation of Neuro-Adipose Connections Increase Blood Pressure Responses in Male Mice Exposed to Early Life Stress
Authors: Dalmasso Carolina , Mounce Sophia , Leachman Jacqueline , Xu Xiu , Loria Analia
Published: September 2019

Visceral adiposity increases sympathetic activation and the risk for obesity-induced hypertension. Experimental stimulation of afferent excitatory signals from adipose tissue contributes to increased sympathetic activation during obesity-induced hypertension as part of a sympatho-excitatory mechanism called the Adipose Afferent Reflex (AAR). Our lab has shown that male mice exposed to maternal separation and early weaning (MSEW), a mouse model that mimics early life stress in humans, display increased sympathetic tone and mean arterial pressure (MAP) when fed high fat diet chronically. Therefore, we hypothesize that the AAR could be implicated in the exacerbated obesity-induced hypertension observed in male MSEW mice. Litters were separated from the dam from postnatal days 2 to 16 and weaned early on day 17. Undisturbed controls (C) were weaned on day 21. After weaning, C and MSEW mice were fed a low fat (LF) or high fat (HF) diet for 16 weeks (10% and 60% Kcal from fat respectively, Research Diets). In mice implanted with carotid catheter for MAP measurements, subcutaneous (sc) or epididymal white adipose tissue (eWAT) were exposed for saline or capsaicin infusions (0.5 nmol/ul; 4 sites; 4ul/min; 2 min; bilateral; n=4-7). Saline infusion in scWAT or eWAT did not change MAP from baseline in any of the groups. Capsaicin infusion in scWAT decreased MAP response in both C and MSEW HF-fed mice compared to LF (p Diet<0.01), whereas infusion in eWAT increased the MAP response in HF-fed MSEW mice compared to C (7±1 vs. -2.5±3 mmHg; p<0.01). After MAP recordings, fat depots were removed to measure capsaicin-induced CGRP release (1 uM capsaicin). In scWAT, CGRP release was decreased in HF compared to LF similarly in both C and MSEW (p Diet<0.01); however, MSEW increased CGRP release compared to C (p MSEW<0.05). In addition, capsaicin infusion increased the number of Fos positive neurons in the paraventricular nucleus of the hypothalamus in MSEW mice fed a HF diet compared to saline (51±6 vs. 26±4; p<0.05), but not in C. Our results show that male MSEW mice fed a HF may display depot-specific afferent signals that influence acute MAP control. Moreover, the AAR could play an important role in the increased sympathetic tone and blood pressure observed in these mice.
Abstract 143: Enhancing Renal Lymphatic Vessel Density Blunts Both Salt-Sensitive and Angiotensin II-Dependent Hypertension in Mice
Authors: Balasubbramanian Dakshnapriya , Konatham Sunitha , Iskander Geina , Engelhaupt Madison , Love Sydney , Tate Winter , Goodlett Bethany L , Wedgeworth Sophie , Baranwal Gaurav , Rutkowski Joseph M , Mitchell Brett M
Published: September 2019

Sodium retention is a hallmark of most forms of experimental hypertension. Renal lymphatics maintain fluid homeostasis by draining cortical interstitial fluid to the draining lymph node. Our lab has previously demonstrated that augmenting renal lymphatics prevents hypertension, but whether this can treat hypertension and whether expanding renal lymphatics alters renal sodium handling remain unknown. Our hypotheses were that augmenting renal lymphatic vessel density after hypertension is established will treat salt sensitive hypertension (SSHTN) and angiotensin II-induced hypertension (AIIHTN) and that this will be accompanied by an increase in urinary sodium excretion. To test our hypotheses, we utilized transgenic mice that overexpress the lymphangiogenic growth factor VEGF-D specifically in the kidney when administered doxycycline (KidVD+ mice). KidVD+ mice and KidVD- littermates were made salt-sensitive by treatment with L-NAME (0.5 mg/mL) for two weeks, followed by a washout period of two weeks, and then given a 4% high salt diet for four weeks. To induce AIIHTN, mice were infused with angiotensin II (490 ng/kg/min) for four weeks. Doxycycline was administered to all mice a week after beginning the high salt diet or a week after angiotensin II infusion. Prior to doxycycline initiation, KidVD- and KidVD+ mice were hypertensive (SSHTN SBP: 130±2 and 134±2 mmHg, respectively; AIIHTN SBP: 125±2 and 128±2 mmHg, respectively). Compared to KidVD- mice, doxycycline administration for three weeks augmented renal lymphatics in KidVD+ mice and significantly decreased blood pressure after four weeks of high salt diet or angiotensin II (SSHTN SBP: 134±4 vs. 125±2 mmHg; p<0.05; AIIHTN: 145±3 vs. 125±5 mmHg; p<0.05). The reduction in blood pressure was accompanied by an increase in urinary fractional excretion of sodium in SSHTN and AIIHTN KidVD+ mice. AIIHTN induced an elevated glomerular filtration rate (GFR) in KidVD- mice while this was reduced in KidVD+ mice; however, GFR was unaltered in SSHTN KidVD+ mice. Thus, augmenting renal lymphatics increased fractional excretion of sodium and lowered blood pressure in both mouse models of hypertension. Augmenting renal lymphatics may be a promising anti-hypertensive and natriuretic therapeutic strategy.
Abstract 150: Obese Hypertensive Pregnant Rats Have Reduced Placental Growth Factor Whereas Increasing It's Levels Decreases Their Blood Pressure
Authors: Spradley Frank T , Palei Ana C , Joo Woo S , Kussie Paul , Tan Adelene Y
Published: September 2019

While epidemiological studies have repeatedly shown that overweight and obesity are associated with hypertension during pregnancy, the mechanisms linking these co-morbidities are not as explored. Reports show reduced levels of the anti-hypertensive and pregnancy-related factor, placental growth factor (PlGF), in obese hypertensive pregnant humans. We tested the hypothesis that obese hypertensive pregnant rats have reduced PlGF whereas increasing its levels reduces their blood pressure. We utilized a genetic model of obesity in rats having heterozygous deficiency of the melanocortin-4 receptor (MC4R-def) compared to wild-type lean controls. By gestational day 19, body mass (341±8 vs 311±7 g), periaortic adipose tissue (10.9±1.1 vs 8.2±0.5 mg), retroperitoneal adipose tissue (4.4±0.4 vs 2.5±0.2 g), circulating levels of leptin (10±1 vs 6±1 ng/mL), and mean arterial blood pressure (116±2 vs 105±2 mmHg) were greater (all P<0.05) in obese (N=17) compared to lean (N=14) pregnant rats. PlGF levels were lower (P<0.05) in serum (61±6 vs. 78±7 pg/mL) and secreted from placental (58±3 vs 71±3 pg/mg) and periaortic adipose tissue (7±1 vs 15±2 pg/mL) explants in obese compared to lean groups. PlGF secretion from retroperitoneal adipose tissue was similar between obese (78±10 pg/mL) and lean (62±12 pg/mL) groups. Vascular expression of the PlGF receptor, vascular endothelial growth factor receptor 1 (VEGFR1), was lower (P<0.05) in aortic tissue (832±60 vs 1106±91 pg/mg) but higher (P<0.05) in small mesenteric arteries (214±23 vs. 151±17 pg/mg) from the obese pregnant rats. Chronic administration of recombinant human (rh)PlGF (180 ug/kg per day) from gestational day 13-19 produced detectable levels of human PlGF in serum from both lean (33±4 pg/mL) and obese (43±4 pg/mL) pregnant rats and reduced (P<0.05) blood pressure in obese (102±3 mmHg) but not in lean (101±3 mmHg) groups. The treatment did not alter maternal body or fat masses or circulating leptin. In summary, PlGF is reduced in MC4R-def obese hypertensive pregnant rats, similar to findings in obese pregnant humans, whereas increasing the levels of PlGF reduced their hypertensive phenotype. Thus, treatment with rhPlGF may prove beneficial in attenuating blood pressure in obese hypertensive pregnancies.
Abstract 151: Post-Partum Hypertension in Response to Acute Kidney Injury During Pregnancy
Authors: Szczepanski Jamie , Spencer Shauna-Kay , Bowles Teylor , Dumas John P , Williams Jan M , Griffin Ashley , Wallace Kedra
Published: September 2019

AKI during pregnancy is associated with high rates of maternal morbidity/mortality as well as fetal loss. Unfortunately women with HELLP (hemolysis, elevated liver, and low platelet) syndrome and preeclampsia are at an increased risk of developing AKI. For most women AKI during pregnancy resolves shortly after pregnancy and the effects have been thought to be temporary. However, new reports suggest that AKI during pregnancy can lead to progression of CKD. Using an established animal model of HELLP syndrome, the objective of the current study was to determine if AKI during pregnancy was associated with hypertension in the post-partum period. On gestational day (GD) 12, mini-osmotic pumps infusing sFlt-1 and sEng were placed into rats to induce HELLP (n=12). A subset of HELLP (n=7) and normal pregnant (NP; n=6) rats underwent bilateral renal ischemia-reperfusion surgery for 45 minutes on GD18. Untreated NP rats served as controls (n=9). All rats delivered on GD21 and were euthanized at post-partum week (PPW) 15. HELLP (6.2±0.08g; p=0.04), NP+AKI (5.3±0.09g; p<0.01) and HELLP+AKI (5.8±0.11g; p<0.01) rat pups were significantly smaller compared to NP rat pups (6.6±0.06g). Blood pressure was significantly increased in NP+AKI rats compared to NP rats (146±3.2 vs. 137±3.9mmHg; p=0.05) and in HELLP compared to NP rats (159±6.2mmHg; p=0.01) at PPW13. GFR was not increased in HELLP compared to NP (p=0.06) but was increased in NP+AKI rats (p=0.03) when measured at PPW14. Immune cells were examined via flow cytometry and NP+AKI had increased infiltrating renal CD4
+
T cells compared to NP rats (11.2% vs. 3.4%; p=0.04). The ratio of M1/M2 macrophages in the kidneys of NP+AKI (19.2%; p=0.01) and HELLP (5.9%; p=0.05) was increased compared to NP rats (2.7%). Currently there are only 2 HELLP+AKI rats that survived to PPW13 (p=0.008) as 71.5% of the group died prior to post-partum day 5. The results from this study suggest that AKI during pregnancy contributes to progressive kidney injury and immune cell infiltration into the kidney. Additionally both NP+AKI and HELLP rats remained hypertensive 3 months post-partum. These results suggest that the cardiovascular and renal affects that occur during pregnancy can have a chronic affect and contribute to the worsening of maternal health.
Abstract 152: Downregulation of Placental Genes are Associated With the Development of Maternal Syndrome in Dahl Salt-Sensitive Rats
Authors: Dasinger John Henry H , Abais-Battad Justine M , Fehrenbach Daniel J , Lund Hayley , Zemaj Jeylan , Alsheikh Ammar J , Mattson David L
Published: September 2019

The Dahl Salt-Sensitive rat maintained on a low salt, casein-based diet (SSC) develops maternal syndrome (hypertension and proteinuria) compared to virgin controls. Our group has previously demonstrated that a substitution of the casein protein for a wheat gluten protein in the rat chow (SSWG) protects the Dahl SS rat from the development of maternal syndrome. This protection is observed in both the blood pressure (141±3 vs 114±4 mmHg,
p
<0.001, SSC vs. SSWG, respectively) and proteinuria (98±16 vs 52±12 mg/day,
p
<0.01). It is also associated with an improvement in uterine artery resistance index (0.9±0.02 vs 0.5±0.04,
p<
0.01) suggesting dietary protein source influences pregnancy in Dahl SS rats. While the exact mechanisms responsible for the development of maternal syndrome are unclear, it is thought that poor placentation is the initiating step in the disease process. Since a substitution of the protein source in the rat chow greatly impacted the phenotype in the Dahl SS rat, we tested the hypothesis that there was differential gene expression in the placental tissue between the SSC rats prone to maternal syndrome compared to the protected SSWG rats. To investigate these phenotypic differences, a PCR array approach was utilized to explore gene expression in placental tissue of both SSC and SSWG rats. Placental tissue from both strains at gestational day 20 was homogenized and RNA isolated to investigate 89 genes related to rat pregnancy and preeclampsia. Using a commercially available PCR array approach identified 4 genes that were differentially expressed between the SSC and SSWG placentas. There was a significant downregulation in expression of
Atp1b1
(0.0018-fold change,
p
<0.01)
, Nos3
(0.13-fold change,
p
<0.005)
, Cdh13
(0.42-fold change,
p
<0.05)
and Cyp26a1
(0.48-fold change,
p
<0.05) in the SSC compared to the SSWG rats. All four of these genes have been demonstrated to play roles in the placentation phase of gestation in other animal models. These results suggest that downregulation of these genes in placentas of the SSC rats, as a result of alterations in dietary protein intake, contributes to the maternal syndrome phenotype and provide avenues for future studies.
Abstract P1115: Decreased Tubuloglomerular Feedback (TGF) Response in High-Fat Diet Induced Obesity
Authors: Monu Sumit R , Wang Hong , Ortiz Pablo
Published: September 2019

Obesity is associated with increased renal and glomerular damage and hypertension, but the mechanisms are not clear. Normally, kidneys autoregulate to keep the glomerular capillary pressure (P
GC
), renal blood flow and glomerular filtration rate in a steady state. In obesity, the kidney loses its autoregulatory capacity, leading to higher P
GC
, renal blood flow and glomerular filtration rate. Together, these may lead to glomerular damage. P
GC
is controlled mainly by the afferent arteriole (Af-Art) resistance. Af-Art resistance in turn is regulated by an intrinsic renal feedback mechanism known as tubuloglomerular feedback (TGF). TGF causes Af-Art constriction in response to an increase in sodium chloride (NaCl) in the macula densa,
via
the Na-K-2Cl cotransporter NKCC2. We previously found that in the Zucker rat model of obesity, TGF was decreased and this was associated with higher blood pressure (BP) and proteinuria. However, it is not known whether obesity induced by a high fat diet in normal Sprague Dawley (SD) rats could also affect TGF. We hypothesized that TGF would be attenuated in obesity caused by 16 weeks of high fat fed (HFD) feeding (60% fat) in SD rats. SD rats fed normal-fat diet (12% fat, NFD) served as control. HFD fed rats exhibited higher body weight (HFD: 833.7±33.3 vs. NFD: 682.3±24.8 grams, p<0.05) and were hypertensive under Inactin anesthesia (mean BP HFD: 131.4±3.6 vs.115.8±3.8 mmHg, p<0.05). We performed
in-vivo
renal micropuncture of individual rat nephrons while measuring stop-flow pressure (P
SF
), an index of P
GC.
P
SF
decreases with an increase in Af-Art resistance. TGF response was measured as a decrease in P
SF
induced by changing the rate of late proximal perfusion from 0 to 40nl/min. Maximal TGF response was significantly smaller in HFD fed rats compared to the NFD rats (HFD: 4.1±0.9 vs. NFD: 10.2±0.6 mmHg, p<0.05) indicating attenuation of TGF by HFD. Baseline P
GC
was higher in HFD rats compared to NFD rats (HFD: 41.6±0.8 vs. NFD: 38.7.2±0.5 mmHg, p<0.05). We conclude that TGF is attenuated in HFD fed obese SD rats and this may contribute to increased renal blood flow and GFR observed in obesity. Hypertension, combined with an attenuated TGF response and increased P
GC
may explain higher renal damage caused by obesity.
Abstract P1118: The Role of Lateral Hypothalamic Leptin Circuitry in Autonomic Control of Cardiovascular Function
Authors: Singh Uday , Toth Brandon A , Saito Kenji , Morgan Donald A , Jiang Jingwei , Rahmouni Kamal , Cui Huxing
Published: September 2019

Obesity is commonly associated with sympathetic overactivity and elevated blood pressure, and accumulating evidence suggests that an adipocyte-derived metabolic hormone, leptin, may plays an important role in these pathological processes, likely through a mechanism of so-called ‘selective leptin resistance’. However, underlying neural circuits through which leptin causes sympathoexcitation and increases blood pressure remain incompletely understood. Here we hypothesized that leptin may acts on a subset of lateral hypothalamic area (LHA) neurons to affect cardiovascular functions. We show that stereotaxic microinfusion of leptin into the LHA dose-dependently increases renal sympathetic nerve activity (RSNA) (% changes from baseline at 4
th
hour: vehicle -25.03 ± 7.09 % vs leptin 100.23 ± 26.94 %, p<0.001) and selective chemogenetic activation of LHA LepR-expressing neurons increase arterial pressure compared to control mice (19.43 ± 0.87 mm of Hg, p<0.05). Consistent with these functional observations, viral-mediated cell type-specific anterograde tracing revealed that LHA LepR-expressing neurons, which are distinct from well-known orexin and MCH neurons, broadly innervate brain regions known for autonomic regulation, including but not limited to paraventricular nucleus, nucleus of solitary tractus, locus coeruleus, and ventrolateral medulla. These findings identify the LHA as a novel brain site critical for leptin to regulate RSNA and arterial pressure.