SDF-1? induction in mature smooth muscle cells by inactivation of PTEN is a critical mediator of exacerbated injury-induced neointima formation.

ABSTRACT: 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? (SDF-1?). We investigated the effects of SDF-1? on resident SMC and bone marrow-derived cells and in mediating neointima formation.Inducible, SMC-specific PTEN knockout mice (PTEN iKO) were bred to floxed-stop ROSA26-?-galactosidase (?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, ?Gal(+) SMC accumulated in the intima and adventitia. Compared with wild-type, PTEN iKO mice exhibited massive neointima formation, increased replicating intimal and medial ?Gal(+)SMC, and enhanced vascular recruitment of bone marrow cells following injury. Inhibiting SDF-1? 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? expression.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? axis is a critical regulator of these events.

SUBMITTER: Nemenoff RA 

PROVIDER: S-EPMC3111081 | biostudies-literature | 2011 Jun

REPOSITORIES: biostudies-literature