SDF-1α Induction in Mature Smooth Muscle Cells by Inactivation of PTEN Is a Critical Mediator of Exacerbated Injury-Induced Neointima Formation

Objective-PTEN inactivation selectively in smooth muscle cells (SMC) initiates multiple downstream events driving neointima formation, including SMC cytokine/chemokine production, in particular stromal cell-derived factor-1 alpha (SDF-1 alpha). We investigated the effects of SDF-1 alpha on resident SMC and bone marrow-derived cells and in mediating neointima formation. Methods and Results-Inducible, SMC-specific PTEN knockout mice (PTEN iKO) were bred to floxed-stop ROSA26-beta-galactosidase (beta Gal) mice to fate-map mature SMC in response to injury; mice received wild-type green fluorescent protein-labeled bone marrow to track recruitment. Following wire-induced femoral artery injury, beta Gal(+) SMC accumulated in the intima and adventitia. Compared with wild-type, PTEN iKO mice exhibited massive neointima formation, increased replicating intimal and medial beta Gal(+)SMC, and enhanced vascular recruitment of bone marrow cells following injury. Inhibiting SDF-1 alpha blocked these events and reversed enhanced neointima formation observed in PTEN iKO mice. Most recruited green fluorescent protein(+) cells stained positive for macrophage markers but not SMC markers. SMC-macrophage interactions resulted in a persistent SMC inflammatory phenotype that was dependent on SMC PTEN and SDF-1 alpha expression. Conclusion-Resident SMC play a multifaceted role in neointima formation by contributing the majority of neointimal cells, regulating recruitment of inflammatory cells, and contributing to adventitial remodeling. The SMC PTEN-SDF-1 alpha axis is a critical regulator of these events. (Arterioscler Thromb Vasc Biol. 2011;31:1300-1308.)