Smooth Muscle LDL Receptor-Related Protein-1 Inactivation Reduces Vascular Reactivity and Promotes Injury-Induced Neointima Formation

Abstract

Objective— Defective smooth muscle expression of LDL receptor-related protein-1 (Lrp1) increases atherosclerosis in hypercholesterolemic mice. This study explored the importance of smooth muscle Lrp1 expression under normolipidemic conditions.

Methods and Results— Smooth muscle cells isolated from control (smLrp1^+/+) and smooth muscle-specific Lrp1 knockout (smLrp1^−/−) mice were characterized based on morphology, smooth muscle marker protein expression levels, and growth rates in vitro. Vascular functions were assessed by aortic constrictive response to agonist stimulation in situ and neointimal hyperplasia to carotid arterial injury in vivo. The smLrp1^−/− smooth muscle cells displayed reduced α-actin and calponin expression and an accelerated growth rate attribtuable to sustained phosphorylation of platelet-derived growth factor receptor (PRGFR) and protein kinase B/Akt. Vasoconstrictive response to agonist stimulation was impaired in aortic rings isolated from smLrp1^−/− mice. Injury-induced neointimal hyperplasia was significantly increased in smLrp1^−/− mice. The increase in neointima was associated with corresponding elevated activation of PDGFR signaling pathway.

Conclusions— Smooth muscle expression of Lrp1 is important in maintaining normal vascular functions under normolipidemic conditions. The absence of Lrp1 expression results in greater smooth muscle cell proliferation, deficient contractile protein expression, impairment of vascular contractility, and promotion of denudation-induced neointimal hyperplasia.