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 6

Decreased PTEN and αSMA expression in coronary arteries exposed to CF-LVADs.

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Decreased PTEN and αSMA expression in coronary arteries exposed to CF-LV...
Coronary arteries from explanted hearts of non–left ventricular assist device (non-LVAD) or continuous-flow LVAD (CF-LVAD) patients were immunofluorescently stained for α-smooth muscle actin (αSMA) (A) and PTEN (C). (A and C) Representative confocal images of stained vessels showing the arterial media (M). Scale bars: 100 μm. (B) Relative area of αSMA expression for the arterial media was measured by ImageJ and averaged from 4 or 5 confocal images (original magnification, ×63) per vessel. (D) Relative area of PTEN staining was determined by ImageJ as described in B. Non-LVAD: N = 13 individual vessels from 7 independent hearts; CF-LVAD: N = 12 individual vessels from 9 independent hearts. Horizontal lines show the mean ± SD. Significant P values are shown, as determined by 2-tailed Student’s t test. (E) Left: Relative area of DAPI expression in the media per vessel was measured by ImageJ and averaged from 4 or 5 confocal images (original magnification, ×63) of media per vessel. Non-LVAD: N = 13 individual vessels; CF-LVAD: N = 12 individual vessels. Middle and Right: The mean gray value within cell boundary ROI for single-cell analysis of medial smooth muscle cells for αSMA (middle) and PTEN (right) levels was determined using ImageJ, as described in Figure 3. Nonatherosclerotic hyperplasia (NAH): N = 180 individual cells from 8 vessels and 5 independent hearts; LVAD: N = 217 individual cells from 7 vessels and 6 independent hearts. #P ≤ 0.0001 by Mann-Whitney 2-tailed t test. Plotted data include the median gray value (horizontal bar), interquartile range (box boundary), and minimum to maximum range of data values (vertical bar).