PTEN deficiency promotes pathological vascular remodeling of human coronary arteries
Karen S. Moulton, Marcella Li, Keith Strand, Shawna Burgett, Penn McClatchey, Rebecca Tucker, Seth B. Furgeson, Sizhao Lu, Bruce Kirkpatrick, Joseph C. Cleveland, Raphael A. Nemenoff, Amrut V. Ambardekar, Mary C.M. Weiser-Evans
Karen S. Moulton, Marcella Li, Keith Strand, Shawna Burgett, Penn McClatchey, Rebecca Tucker, Seth B. Furgeson, Sizhao Lu, Bruce Kirkpatrick, Joseph C. Cleveland, Raphael A. Nemenoff, Amrut V. Ambardekar, Mary C.M. Weiser-Evans
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Research Article Vascular biology

PTEN deficiency promotes pathological vascular remodeling of human coronary arteries

Abstract

Phosphatase and tensin homolog (PTEN) is an essential regulator of the differentiated vascular smooth muscle cell (SMC) phenotype. Our goal was to establish that PTEN loss promotes SMC dedifferentiation and pathological vascular remodeling in human atherosclerotic coronary arteries and nonatherosclerotic coronary arteries exposed to continuous-flow left ventricular assist devices (CF-LVADs). Arteries were categorized as nonatherosclerotic hyperplasia (NAH), atherosclerotic hyperplasia (AH), or complex plaque (CP). NAH coronary arteries from CF-LVAD patients were compared to NAH coronaries from non-LVAD patients. Intimal PTEN and SMC contractile protein expression was reduced compared with the media in arteries with NAH, AH, or CP. Compared with NAH, PTEN and SMC contractile protein expression was reduced in the media and intima of arteries with AH and CP. NAH arteries from CF-LVAD patients showed marked vascular remodeling and reduced PTEN and α-smooth muscle actin (αSMA) in medial SMCs compared with arteries from non-LVAD patients; this correlated with increased medial collagen deposition. Mechanistically, compared with ApoE–/– mice, SMC-specific PTEN-null/ApoE–/– double-knockout mice exhibited accelerated atherosclerosis progression and increased vascular fibrosis. By microarray and validated quantitative RT-PCR analysis, SMC PTEN deficiency promotes a global upregulation of proinflammatory and profibrotic genes. We propose that PTEN is an antiinflammatory, antifibrotic target that functions to maintain SMC differentiation. SMC loss of PTEN results in pathological vascular remodeling of human arteries.

Authors

Karen S. Moulton, Marcella Li, Keith Strand, Shawna Burgett, Penn McClatchey, Rebecca Tucker, Seth B. Furgeson, Sizhao Lu, Bruce Kirkpatrick, Joseph C. Cleveland, Raphael A. Nemenoff, Amrut V. Ambardekar, Mary C.M. Weiser-Evans

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Figure 4

Accelerated atherosclerosis development in inducible, smooth muscle cell–specific PTEN-KO mice.

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Accelerated atherosclerosis development in inducible, smooth muscle cell...
Myh11-CreERT2; ApoE–/– (WT) and PTEN-iKO; ApoE–/– (KO) mice were injected with tamoxifen. Two weeks after the last tamoxifen injection mice were placed on normal chow (nc) or Western diet (0.15% cholesterol; wd) for 8 weeks. N = 6 WT nc, WT wd, KO nc; N = 5 KO wd. (A) The amount of atherosclerotic plaque in the aorta was measured as the percentage area of Sudan IV+ (red) plaques per area of en face–mounted descending aorta (DA). Representative aortas from each genotype and diet cohort are shown (bottom). (B) The area of intimal plaques was measured at 6 equally spaced levels in the aortic sinus and averaged. The mean area (mm2) of the aortic sinus plaque is plotted for each mouse. Representative H&E images of the aortic sinus plaques in WT and KO mice are shown for groups fed the normal chow or Western-type diet (bottom); black dashed lines outline area of plaque. (C) Aortic sinus (A.S.) plaque areas are plotted at each section level to perform area under the curve (AUC) analysis, as a correlate of plaque size. For all panels, gray data points indicate WT samples, black data points indicate KO samples, and horizontal lines indicate the median and interquartile range. **P < 0.01 by Kruskal Wallis with Dunn’s posttest comparisons.