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

RA Nemenoff, H Horita, AC Ostriker… - … , and vascular biology, 2011 - Am Heart Assoc
RA Nemenoff, H Horita, AC Ostriker, SB Furgeson, PA Simpson, V VanPutten, J Crossno…
Arteriosclerosis, thrombosis, and vascular biology, 2011Am Heart Assoc
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-1α (SDF-1α). We investigated the effects
of SDF-1α 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-β-galactosidase (βGal) mice to fate-map mature SMC in …
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-1α (SDF-1α). We investigated the effects of SDF-1α 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-β-galactosidase (βGal) 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, βGal(+) SMC accumulated in the intima and adventitia. Compared with wild-type, PTEN iKO mice exhibited massive neointima formation, increased replicating intimal and medial βGal(+)SMC, and enhanced vascular recruitment of bone marrow cells following injury. Inhibiting SDF-1α 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-1α 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-1α axis is a critical regulator of these events.
Am Heart Assoc