Marfan syndrome (MFS) is a connective tissue disorder (CTD) associated with mutations in fibrillin-1 ( Fbn1), leading to chronic systemic increases in transforming growth factor-β (TGF-β) availability and signaling that could lead to aortic wall weakening and aneurysm/rupture. 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 systemic vascular dysfunction including cerebrovascular complications such as stroke, and cerebral aneurysm. Therefore, we hypothesized that Fbn1 mutation ( Fbn1C1041G/+) is associated with systemic vascular dysfunction, BBB permeability, neuroinflammation, neurobehavioral alterations, and impaired glutamate homeostasis, leaving the brain more vulnerable to mild traumatic brain injury (mTBI). Our experimental groups included: 6M-old male and female MFS ( Fbn1C1041G/+) and C57BL/6 (WT) control, and middle-aged 12M WT mice (N=3-10/group, P < 0.05). In vivo ultrasound imaging analyzed by two blinded investigators demonstrated increased aortic root diameters and stiffness in MFS mice compared to 6M and 12M WT mice, where MFS male diameters were affected more than females. Vascular dysfunction measured by blood flow velocity (BFV) extended to the left pulmonary artery where 6M MFS and 12M WT mice were reduced compared to 6M WT mice. This reduction continued through decreased posterior cerebral artery BFV in MFS males, where MFS females were comparable to 6 and 12M WT females. In 6M MFS male mice, Evans blue extravasation and Immunoglobulin G staining demonstrated increased BBB permeability in the hippocampus to large and small molecules, respectively, as well as to small molecules in the lateral hypothalamus as compared to 6M WT and like 12M WT. In adjacent sections, iba-1-stained cells had morphologies indicative of reactive microglia. In vivo electrochemical recordings in the hippocampus showed a trend towards lowered peak glutamate amplitudes and elevated baseline glutamate concentrations in MFS and 12M WT mice demonstrating disrupted glutamate homeostasis. Furthermore, exogenous TGF-β applied in the lateral hippocampus of 6M WT males revealed an evoked glutamate response that may support this elevated baseline in MFS 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 like 6M MFS and 12M WT mice. These novel findings signify MFS as a condition of systemic vascular dysfunction and pre-mature cerebrovascular aging phenotype with more vulnerability to brain injury. Funding: NIH-R36AG083385, Valley Research Partnership-P1A-5012, NIH-R15HL145646, NIH-R01NS100793, Midwestern Graduate Funds, Phoenix Children’s Hospital Leadership Circle, Graduate and Professional Council Research and Projects Grant. This is the full abstract presented at the American Physiology Summit 2024 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.
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Sep 24, 2024
Mitzi Marlotte Van Andel + 13
Open Access