Abstract 302: Smooth Muscle Cell Mineralocorticoid Receptors Directly Mediate Aldosterone-induced Remodeling After Vascular Injury Via Type 1 Vegf Receptors
Background and Significance Endothelial damage initiates vascular remodeling with smooth muscle cell (SMC) proliferation and vascular fibrosis. Excessive remodeling, as in restenosis after vascular procedures or atherosclerosis, limits blood flow to distal tissues. In animals, aldosterone (aldo) infusion enhances remodeling which is reversed by aldo antagonists, implicating the mineralocorticoid receptor (MR). We previously showed that MR is expressed in SMC and that aldo induces the type 1 VEGF receptor (VEGFR1) in injured vessels.
Hypothesis and Results We hypothesize that aldo promotes pathological vascular remodeling by directly activating MR in SMC and promoting SMC proliferation via VEGFR1 signaling. We show in vivo that aldo does not affect re-endothelialization after injury supporting our focus on SMC. To test this hypothesis we measured aldo-induced remodeling after wire carotid injury in mice with inducible SMC-specific deletion of MR (SMC-MR-KO). The 80% increase in SMC proliferation with aldo in control littermates is completely prevented in SMC-MR-KO mice (p<0.005, n=11). To examine the mechanism, mouse carotid SMC were treated with aldo in vitro producing a dose dependent proliferative response (1,5,10 and100nM aldo, 9%±2, 17%±3, 21%±6, and 25%±7 vs control, respectively, p<0.05, n=8). The increase in proliferation with 10 nM aldo+IgG was completely inhibited by treatment with specific VEGFR1-blocking antibody (Ab, p=0.04, n=8). Immunohistochemistry of carotid vessels reveals that VEGFR1 is induced in SMC after injury and further enhanced by aldo (55%±0.5 increase with injury, 74%± 0.5 with aldo+injury vs uninjured control, p<0.05, n=8).We examined the role of VEGFR1 in vivo and VEGFR1 blockade significantly reduces aldo-induced SMC proliferation after injury (46%±4 decrease vs aldo+IgG, p<0.05, n=9). Tail cuff measurements reveal no difference in blood pressure with any of the treatments.
Conclusions These data support that SMC MR directly mediates aldo-induced vascular remodeling independent blood pressure. The mechanism involves VEGFR1 that is induced on SMC in the area of injury. This study supports exploring VEGFR1-blocking drugs to prevent pathological vascular remodeling induced by aldo in humans.
- © 2013 by American Heart Association, Inc.