JOURNAL ARTICLE

Targeted deletion of PTEN in smooth muscle cells results in vascular remodeling and recruitment of progenitor cells through induction of stromal cell-derived factor-1alpha

Raphael A Nemenoff, Peter A Simpson, Seth B Furgeson, Nihal Kaplan-Albuquerque, Joseph Crossno, Pamela J Garl, James Cooper, Mary C M Weiser-Evans
Circulation Research 2008 May 9, 102 (9): 1036-45
18340011
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 PTEN(LoxP/LoxP) mice to mice expressing Cre recombinase under the control of the SM22alpha 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)-1alpha and medial and intimal cells coexpressing SM-alpha-actin and CXCR4, the SDF-1alpha receptor, was detected in SMC PTEN-depleted mice. PTEN deficiency in cultured aortic SMCs induced autocrine growth through increased production of SDF-1alpha. Blocking SDF-1alpha 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-1alpha production. SDF-1alpha production by other cell types is regulated by the transcription factor hypoxia-inducible factor (HIF)-1alpha. We found SMC nuclear HIF-1alpha expression in PTEN-depleted mice and increased nuclear HIF-1alpha in PTEN-deficient SMCs. Small interfering RNA-mediated downregulation of HIF-1alpha reversed SDF-1alpha induction by PTEN depletion and inhibition of phosphatidylinositol 3-kinase signaling blocked HIF-1alpha and SDF-1alpha 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-1alpha-mediated SDF-1alpha/CXCR4 axis, thus identifying PTEN as a target for the inhibition of pathological vascular remodeling.

Full Text Links

Find Full Text Links for this Article

Discussion

You are not logged in. Sign Up or Log In to join the discussion.

Related Papers

Remove bar
Read by QxMD icon Read
18340011
×

Save your favorite articles in one place with a free QxMD account.

×

Search Tips

Use Boolean operators: AND/OR

diabetic AND foot
diabetes OR diabetic

Exclude a word using the 'minus' sign

Virchow -triad

Use Parentheses

water AND (cup OR glass)

Add an asterisk (*) at end of a word to include word stems

Neuro* will search for Neurology, Neuroscientist, Neurological, and so on

Use quotes to search for an exact phrase

"primary prevention of cancer"
(heart or cardiac or cardio*) AND arrest -"American Heart Association"