Curry-Koski, T. | Search bioRxiv

bioRxiv2024

Genetic Manipulation of Caveolin-1 in the Mouse Model of Marfan Syndrome Associated Aortic Root Aneurysm: Effects on Endothelial and Smooth Muscle Function

Marfan Syndrome (MFS) is a systemic connective tissue disorder caused by mutations in the gene encoding for the large glycoprotein Fibrillin-1 (Fbn1), leading to wide-spectrum clinical manifestations, with the most life-threatening being aortic root aneurysm. MFS aortic aneurysm is known to be associated with reduced endothelial nitric oxide synthase (eNOS)-mediated nitric oxide (NO) production. Previous studies have shown that caveolin-1 (Cav1), a coat protein of caveolae structure on the plasma membrane, acts as a negative regulator of eNOS activity. This suggests that Cav1 may play a role in the development of aortic root aneurysm in MFS by modulating eNOS activity. In this study, we investigated the role of Cav1 in regulating aortic smooth muscle and endothelial function, aortic wall elasticity, and wall strength by generating MFS mice (FBN1+/Cys1041Gly) lacking Cav1 gene expression (MFS/Cav1KO). Our data show that ablation of the Cav1 gene results in a significant decrease in aortic smooth muscle contraction in response to the vasoconstricting agent phenylephrine seemingly due to a marked increase in NO production within the aortic wall. We also showed that acetylcholine-induced vasorelaxation was increased in MFS/Cav1KO mice potentially through the endothelial nitric oxide-dependent mechanism, further confirming inhibitory role of Cav1 on endothelial NO production. In addition, aortic wall elastin fiber structure and strength were markedly improved in male MFS/Cav1KO mice. This study demonstrates the regulatory role of Cav1 during the development of aortic root aneurysm in MFS mice through its effects on smooth muscle and endothelial functions in an NO-dependent manner.

physiology↗

bioRxiv2024

Cerebral Microvascular Density, Permeability of the Blood-Brain Barrier, and Neuroinflammatory Responses Indicate Early Aging Characteristics in a Marfan Syndrome Mouse Model

Marfan Syndrome (MFS) is a connective tissue disorder due to mutations in fibrillin-1 (Fbn1), where a Fbn1 missense mutation (Fbn1C1039G/+) can result in systemic increases in the bioavailability and signaling of transforming growth factor-{beta} (TGF-{beta}). In a well-established mouse model of MFS (Fbn1C1041G/+), pre-mature aging of the aortic wall and the progression of aortic root aneurysm are observed by 6-months-of-age. TGF-{beta} signaling has been implicated in cerebrovascular dysfunction, loss of blood-brain barrier (BBB) integrity, and age-related neuroinflammation. We have reported that pre-mature vascular aging in MFS mice could extend to cerebrovasculature, where peak blood flow velocity in the posterior cerebral artery (PCA) of 6-month-old (6M) MFS mice was reduced, similarly to 12-month-old (12M) control mice. Case studies of MFS patients have documented neurovascular manifestations, including intracranial aneurysms, stroke, arterial tortuosity, as well as headaches and migraines, with reported incidence of pain and chronic fatigue. Despite these significant clinical observations, investigation into cerebrovascular dysfunction and neuropathology in MFS remains limited. Using 6M-control (C57BL/6) and 6M-MFS (Fbn1C1041G/+) and healthy 12M-control male and female mice, we test the hypothesis that abnormal Fbn1 protein expression is associated with altered cerebral microvascular density, BBB permeability, and neuroinflammation in the PCA-perfused hippocampus, all indicative of a pre-mature aging brain phenotype. Using Glut1 staining, 6M-MFS mice and 12M-CTRL similarly present decreased microvascular density in the dentate gyrus (DG), cornu ammonis 1 (CA1), and cornu ammonis 3 (CA3) regions of the hippocampus. 6M-MFS mice exhibit increased BBB permeability in the DG, CA1, and CA3 as evident by Immunoglobulin G (IgG) staining, which was more comparable to 12M-CTRL mice. 6M-MFS mice show a higher number of microglia in the hippocampus compared to age-matched control mice, a pattern resembling that of 12M-CTRL mice. This study represents the first known investigation into neuropathology in a mouse model of MFS and indicates that the pathophysiology underlying MFS leads to a systemic pre-mature aging phenotype. This study is crucial for identifying and understanding MFS-associated neurovascular and neurological abnormalities, underscoring the need for research aimed at improving the quality of life and managing pre-mature aging symptoms in MFS and related connective tissue disorders.

neuroscience↗