Abstract 15572: BRCA1 is a Novel Regulator of Vascular Smooth Muscle Phenotypic Modulation and a Target for Blood Pressure Regulation and Vascular Remodeling
Phenotypic switching of vascular smooth muscle cells (VSMCs) from a contractile towards a synthetic phenotype is believed to play a critical role in the development of aberrant vascular remodelling. Given the critical role of BRCA1 as a regulator of cell cycle control and transcriptional regulation, we hypothesized that it may be a novel target to modulate VSMC phenotypic modulation, and through this mechanism may attenuate blood pressure. In the first series of experiments, VSMCs were isolated from the aortae of spontaneously hypertensive rats (SHR) and studied in culture. Compared VSMCs from age- and sex-matched normotensive controls, VSMCs from SHRs exhibited marked phenotypic modulation identified by a reduction in the expression of the contractile proteins, α-smooth muscle actin (α-SMA) and smooth muscle 22α (SM22α), in conjunction with increased proliferation and migration capacity and reduced expression of BRCA1. In gain-of-function studies, adenoviral BRCA1 (Ad-BRCA1) overexpression markedly attenuated VSMC phenotypic modulation and abolished PDGF-BB-induced reduction in VSMC expression of contractile proteins (α-SMA, SM22a, smooth muscle myosin heavy chain, and calponin) and attenuated the proliferation and migration capacity of VSMCs. Mechanistically, this effect was mediated via the phosphorylation of PI3K/Akt by BRCA1. To evaluate the in vivo significance, Ad-BRCA1 or Ad-null was injected into 8-week old SHRs. Strikingly, gene delivery of BRCA1 markedly reduced blood pressure as assessed by radiotelemetry (156±11/115±9 mmHg vs. 175±10/131±9 mmHg, p<0.001), and attenuated phenotypic switching in VSMCs isolated from Ad-BRCA-1-treated vs. Ad-null-treated mice. Furthermore, BRCA1 overexpression in VSMCs resulted in a marked reduction in AT1 expression and AT1-mediated generation of reactive oxygen species. We demonstrate a completely novel and previously unrecognized role of BRCA1 as a regulator of VSMC differentiation and phenotypic modulation in hypertension. BRCA1-based gene or cell therapy represents a target for vascular remodelling and blood pressure control.
- © 2012 by American Heart Association, Inc.