Sex-dependent Cerebrovascular Aging and Vulnerability to Traumatic Brain Injury in a Transgenic Mouse Model of a Fibrillin-1 Associated Connective Tissue Disorder
Authors: Curry Tala , Barrameda Mary-Eunice , Curtin Liam , Hair Caitlin , Krishna Gokul , Sabetta Zackary , Thomas Theresa , Esfandiarei Mitra 
Published: May 2023

Marfan syndrome (MFS) is a connective tissue disorder (CTD) associated with mutations in fibrillin-1 (Fbn1), leading to systemic increases in transforming growth factor-β (TGF-β) availability and signaling that induces an accelerated vascular aging phenotype with known peripheral vascular dysfunction by 6-months (6M) of age in Fbn1 C1041G/+ (MFS) mice. TGF-β has been implicated in cerebrovascular dysfunction, loss of blood-brain barrier (BBB) integrity, age-related neuroinflammation and neurological deficits. Improvements in MFS treatment and life expectancy have uncovered a risk for cerebrovascular complications such as stroke, and cerebral aneurysm, predominantly in the posterior cerebral artery (PCA). CTDs have shown unmasking events via mild traumatic brain injury (mTBI), where patients display increased severity and recovery times. Cerebrovascular dysfunction and neuropathology have been minimally investigated in MFS. We hypothesized that abnormal Fbn1 protein expression is associated with a sex-dependent accelerated aging phenotype in the aorta, cerebrovasculature, BBB permeability, neuroinflammation, behavior, and glutamate homeostasis, leaving the brain more vulnerable to mTBI. Male and female 6M MFS, 6M C57BL/6 (WT) control, and middle-aged 12M WT mice were utilized. In vivo ultrasound imaging demonstrated increased aortic root diameters and stiffness in MFS mice compared to 6M WT mice, like 12M WT, where MFS males were affected more than females. Aortic results were associated with decreased PCA blood flow velocity in MFS males, where MFS females were similar to 6 and 12M WT female mice. In 6M MFS mice, Evans blue extravasation and Immunoglobulin G staining demonstrated increased BBB permeability in the hippocampus to large and small molecules, respectively, as compared to WT and like 12M WT. In adjacent sections, iba-1 stained cells had morphologies indicative of reactive microglia. Acute glial activation and BBB permeability can disrupt glutamate homeostasis, where in vivo electrochemical recordings in the hippocampus showed slower glutamate clearance and elevated baseline glutamate concentrations in MFS and 12M WT mice. Higher neurobehavioral severity scale (NSS) scores in 6M MFS mice suggested neurobehavioral alterations that were more like 12M WT. Midline fluid percussion was used to induce mTBI, where 6M MFS male mice and both female groups required a 15% lower pressure to induce mTBI righting reflex times (5-10 minutes) compared to 6M WT male mice. Mice were evaluated at 1-day post injury, where BBB permeability to large and small molecules and microglia activation were increased, glutamate clearance was slowed, and NSS scores were increased compared to 6M WT and were similar to 6M MFS and 12M WT mice. These novel findings signify MFS as a disease of accelerated cerebrovascular aging phenotype and demonstrate potential vulnerability to injury, where chronic TGF-β dysregulation may be a critical regulator of age-related pathology. Valley_Research_Partnership-P1A-5012, NIH-R15HL145646, NIH-R01NS100793, Midwestern Graduate Funds 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.