Targeted Deletion of PTEN in Smooth Muscle Cells Results in Vascular Remodeling and Recruitment of Progenitor Cells Through Induction of Stromal Cell–Derived Factor-1α

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Abstract
We previously showed that changes in vascular smooth muscle cell (SMC) PTEN/Akt signaling following vascular injury are associated with increased SMC proliferation and neointima formation. In this report, we used a genetic model to deplete PTEN specifically in SMCs by crossing PTENLoxP/LoxP mice to mice expressing Cre recombinase under the control of the SM22α promoter. PTEN was downregulated with increases in phosphorylated Akt in major vessels, hearts, and lungs of mutant mice. SMC PTEN depletion promoted widespread medial SMC hyperplasia, vascular remodeling, and histopathology consistent with pulmonary hypertension. Increased vascular deposition of the chemokine stromal cell–derived factor (SDF)-1α and medial and intimal cells coexpressing SM-α-actin and CXCR4, the SDF-1α receptor, was detected in SMC PTEN-depleted mice. PTEN deficiency in cultured aortic SMCs induced autocrine growth through increased production of SDF-1α. Blocking SDF-1α attenuated autocrine growth and blocked growth of control SMCs induced by conditioned media from PTEN-deficient SMCs. In addition, SMC PTEN deficiency enhanced progenitor cell migration toward SMCs through increased SDF-1α production. SDF-1α production by other cell types is regulated by the transcription factor hypoxia-inducible factor (HIF)-1α. We found SMC nuclear HIF-1α expression in PTEN-depleted mice and increased nuclear HIF-1α in PTEN-deficient SMCs. Small interfering RNA–mediated downregulation of HIF-1α reversed SDF-1α induction by PTEN depletion and inhibition of phosphatidylinositol 3-kinase signaling blocked HIF-1α and SDF-1α upregulation induced by PTEN depletion. Our data show that SMC PTEN inactivation establishes an autocrine growth loop and increases progenitor cell recruitment through a HIF-1α–mediated SDF-1α/CXCR4 axis, thus identifying PTEN as a target for the inhibition of pathological vascular remodeling.