Abstract 20966: Increasing Cav1.2 in Smooth Muscle Cells Has Different Effects on Vascular Remodeling Dependent of Insults

Abstract

Introduction: Increasing Calcium (Ca 2+ ) influx through the L-type Ca 2+ channel (Cav1.2) increases smooth muscle cell (SMC) contractility while the loss of Cav1.2 is associated with enhanced SMC remodeling. However, increasing Ca 2+ influx into SMCs through non-Cav1.2 routes is often associated with enhanced vascular remodeling under pathological conditions. Whether increasing Cav1.2 in SMCs may inhibit or promote SMC remodeling is unclear. Hypothesis: Increasing Cav1.2 in SMC protects SMCs from remodeling. Methods: Transgenic mice with SMC-specific overexpression of Cavβ2a and control mice were subjected to carotid artery ligation or aneurysm induction (high fat feeding for 2 months and then HFD+AngII infusion for 1 month) to study vascular remodeling. Results: 1. The Cav1.2 current in SMCs from middle cerebral artery was increased by 98.5±5.4%; 2. The left common carotid artery (LCCA) close to the internal and external arterial bifurcation were completely ligated. After ligation for 3 weeks, there were less thickening of the media and less neointima formation in LCCA region proximal to the ligation in TG (n=8) than in control (n=8) mice; in accordance, there were less EdU labelled cells in TG. The surface area of TG SMCs was not increased as such as in the control. 3. HFD+AngII induces higher frequency (10/10 in TG vs. 4/13 in control) of aneurysm/aortic dilation segments. Among the mice with aortic aneurysm/dilation, the average number of segments of aneurysm/arotic dilation in each mouse was higher in TG (2.7±0.2) than in control (1.3±0.2) mice. The TG mice had thinner vascular wall, larger aneurysmal area accompanied with more severe elastin and middle layer degradation, and more inflammatory cell infiltration in the aortic aneurysm/dilation region than control mice. 4. Rat smooth muscle cells in culture infected with Cavβ2a-GFP adenoviruses (MOI=10) had less proliferation (both total number of cells and EdU + cells) but more death (LDH and TUNEL+) than rat SMCs infected with AdGFP (MOI=10). Less collagen synthesis was observed in rat SMCs infected with Ad Cavβ2a-GFP. Conclusions: Increased Cav1.2 in SMCs may inhibit or promote vascular smooth muscle remodeling depending on the injury nature.