Matricellular protein CCN3 in vascular homeostasis
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SUMMARY Aortic homeostasis is essential for vascular health. The vascular endothelium is a vital organ whose health is essential to normal vascular physiology; when dysregulated, it becomes a critical factor in the pathogenesis of a variety of vascular diseases. Growing evidence indicates that endothelial cells (ECs) play an underappreciated role in the development and progression of thoracic aortic aneurysm and dissection (TAAD). Most notably, compromised barrier integrity has been implicated as a precursor to the development of TAA. Work from our laboratory has led to the appreciation that a member of Cellular Communication Network (CCN) gene family, CCN3, serves as an important regulator of vascular health. However, the precise physiological role of CCN3 in vivo as well as the fundamental mechanisms responsible for CCN3’s action remain largely undefined. Recently, our preliminary studies suggest that CCN3 serves as an endogenous inhibitor of TAAD. Recently, our preliminary studies suggest that endothelial dysfunction due to CCN3 deficiency predisposes animals to thoracic aortic aneurysm and dissection (TAAD). In a mouse model of Marfan syndrome (Fbn1mgR/mgR), global deficiency of CCN3 deficiency exacerbates thoracic aortic aneurysm (TAA) in Marfan mice characterized by increased aortic root and ascending thoracic aortic dilation, elevated incidence of vessel dissection, and, as a consequence, enhanced mortality. Similar findings were obtained when challenging animals with angiotensin II (Ang II). Endothelial restricted knockout mice (EC CCN3-/-) subjected to Ang II infusion exhibited augmented aortic root and thoracic aortic dilation along with an elevated severity of aortic wall destruction. Mechanistically, our initial bulk RNAseq studies suggested that loss of CCN3 perturbs vascular junction and causes aberrant activation of signaling pathways involved in inflammation. Our subsequent in vivo and in vitro studies further support that key factors secondary to CCN3 deficiency (endothelial barrier disruption, inflammation, reactive oxygen species (ROS)) cause endothelial dysfunction and play a pivotal role in TAAD development and progression. These observations provide the foundation for the central hypotheses of this application: CCN3 serves as a critical physiological regulator for the maintenance of endothelial function essential for the prevention of TAAD. Studies in this proposal will rigorously address this hypothesis. The role of endothelial CCN3 in mitigating TAAD will be fully characterized. Mechanistic basis of how CCN3 deficiency leads to endothelial dysfunction will be investigated. The results of these studies will elucidate the role of CCN3 in controlling endothelial function and the mechanisms underlying its ability to promote endothelial barrier integrity and limit inflammation.
