Hyperaldosteronism induces vascular injury and hypertension via CCL5/CCR5 and Nox1-derived reactive oxygen species
Authors: Costa Rafael , Alves Juliano , Santos Débora , Awata Wanessa , Singh Shubhnita , Barbosa Gabriela , Bruder-Nascimento Ariane , Ho Jacqueline , Bruder-Nascimento Thiago 
Published: May 2023

Hyperaldosteronism (HA) is the most frequent cause of endocrine hypertension, however the mechanisms of the genesis of hypertension are not fully understood. CCL5 is a potent pro-inflammatory and chemotactic molecule produced by endothelial and vascular smooth muscle cells and its main actions occur via C-C Motif Chemokine Receptor 5 (CCR5). Herein, we hypothesize that HA leads to hypertension and vascular injury via CCL5/CCR5 and Nox1 dependent mechanisms. 10-12-weeks-old male wild type (CCR5+/+) and CCR5 receptor knockout (CCR5-/-) mice were infused with aldosterone for 14 days (600ug/Kg/day via osmotic mini-pump). Vascular function was studied in endothelium-intact thoracic aortae and blood pressure was analyzed by radiotelemetry. Mouse endothelial cells (MEC) was used to evaluate the molecular mechanisms by which CCL5 induces endothelial dysfunction. HA increased circulating CCL5 levels [Vehicle: 7.41±1.6 vs. HA: 13.2±1.4 (pg/mL)] and reduced acetylcholine (ACH)-induced vasodilation (% relaxation) in CCR5+/+, which was abolished by inhibiting Nox1 (NOXA1ds, 10 μM) [Vehicle: 91.2±2.1 vs. HA: 42.7±3.9 vs. HA+NOXA1ds: 89.7±1.9]. To understand whether CCL5 induces endothelial dysfunction via CCR5 and Nox1 activation, aortae were incubated with CCL5 (100 ng/mL for 24 h) and concentration response curves to ACH was built and Nox1 expression was analyzed. CCL5 treatment significantly reduced ACH response and increased Nox1 protein expression, which were blunted by CCR5 receptor antagonist (Maraviroc, 40 μM) or NOXA1ds, indicating that CCL5 affects endothelial function dependent on CCR5 and Nox1. Next, we found that CCR5-/- mice are protected from HA-induced endothelial dysfunction and hypertension [mean blood pressure (mmHg) – before HA: 100.8±0.4 vs. after HA: 106.1±1.9]. On mechanistic levels, we found that CCL5 leads to NF-κB activation, induces reactive oxygen species generation (superoxide anion and increased NADPH oxidase activity), and increases expression of pro-inflammatory genes (TNF-α, IL-6, ICAM, and VCAM), which was associated with higher macrophage adhesion to MEC, such effects were prevented by blocking CCR5 with Maraviroc. In summary, these findings reveal a novel signaling pathway in vascular injury and hypertension associated with HA, CCL5 activates CCR5 stimulating NF-κB and Nox1 expression and activity, which in turn, leads to vascular damage and hypertension. Our study places CCR5 as an attractive target to reduce cardiovascular risk in HA.

NHLBI-R00 (R00HL14013903), AHA-CDA (CDA857268), Vascular Medicine Institute, the Hemophilia Center of Western Pennsylvania Vitalant, and Children's Hospital of Pittsburgh of the UPMC Health System.

This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.