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PTEN deficiency promotes pathological vascular remodeling of human coronary arteries
Karen S. Moulton, … , Amrut V. Ambardekar, Mary C.M. Weiser-Evans
Karen S. Moulton, … , Amrut V. Ambardekar, Mary C.M. Weiser-Evans
Published February 22, 2018
Citation Information: JCI Insight. 2018;3(4):e97228. https://doi.org/10.1172/jci.insight.97228.
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Research Article Vascular biology

PTEN deficiency promotes pathological vascular remodeling of human coronary arteries

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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 2

PTEN and α-smooth muscle actin (αSMA) expression in human atherosclerosis.

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PTEN and α-smooth muscle actin (αSMA) expression in human atherosclerosi...
(A) Hematoxylin and eosin (H&E; top panels) and PTEN (green) and αSMA (red) stained confocal images (bottom panels) of lesions representing nonatherosclerotic hyperplasia (NAH), atherosclerotic hyperplasia (AH; intima > 200 μm), or complex plaque (CP). Black dashed lines delineate the arterial media (M). I = arterial intima. Scale bars: 200 μm. (B) PTEN (green; left) and αSMA (red; right) stained confocal images of NAH (left in each group), AH (middle in each group), and CP (right in each group) lesions. PTEN and αSMA levels are more abundant in medial (M) smooth muscle cells (SMCs) compared with intimal (I) SMCs and are decreased in atherosclerotic lesions (AH, CP) compared with NAH lesions. Scale bars: 25 μm. (C) Relative area of PTEN expression in the arterial media (M) or intima (I) for a vessel lesion was measured by ImageJ and averaged from 4 or 5 confocal images (original magnification, ×63) of media and intima per vessel. (D) Relative area of αSMA staining was determined by ImageJ as described in C. NAH: N = 13 individual vessels from 7 independent hearts; AH: N = 16 individual vessels from 10 independent hearts; CP: N = 14 individual vessels from 11 independent hearts. Horizontal lines represent the mean ± SD. *P ≤ 0.05, **P ≤ 0.01, ***P ≤ 0.001, #P ≤ 0.0001, by ANOVA with Bonferroni’s posttest multiple comparison test.

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