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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 3

Single-cell analysis of PTEN and smooth muscle myosin heavy chain (SMMHC) α-smooth muscle actin (αSMA) expression in medial SMCs.

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Single-cell analysis of PTEN and smooth muscle myosin heavy chain (SMMHC...
(A) Representative PTEN (green) and SMMHC (red) stained confocal images of lesions representing nonatherosclerotic hyperplasia (NAH), atherosclerotic hyperplasia (AH; intima > 200 μm), or complex plaque (CP); merged images shown. M = arterial media; I = arterial intima. (B) Relative area of DAPI expression in the media per vessel was measured by ImageJ 1.47v as a measure of cellularity and averaged from 4 or 5 confocal images (original magnification, ×63) of media per vessel. 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. (C) Representative confocal images of arterial media from NAH vessels immunofluorescently stained for PTEN (green; left) and αSMA (red; right); nuclei are stained with DAPI (blue). White dashed lines represent cell boundaries for ROI measurements. PTEN and SMMHC/αSMA levels within cell boundary ROI were measured by ImageJ 1.47v as described in Methods. (D) The mean gray value within cell boundary ROI for single-cell analysis of medial smooth muscle cells (SMCs) for SMMHC (left) and PTEN (right) levels was determined using ImageJ. NAH: N = 361 individual cells from 8 vessels and 5 independent hearts; AH: N = 294 individual cells from 7 vessels and 6 independent hearts; CP: N = 286 individual cells from 6 vessels and 5 independent hearts. ***P ≤ 0.001. Plotted data include the median gray value (horizontal bar), interquartile range (box boundary) and minimum to maximum range of data points (vertical bar). (E) The mean gray value within cell boundary ROI for single-cell analysis of medial SMCs for αSMA (left) and PTEN (right) levels was determined using ImageJ. NAH: N = 196 individual cells from 6 vessels and 6 independent hearts; AH: N = 197 individual cells from 6 vessels and 5 independent hearts; CP: N = 195 individual cells from 6 vessels and 5 independent hearts. ***P ≤ 0.001 by Kruskal Wallis with Dunn’s posttest comparisons.

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