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.

Exosomes from nicotine-stimulated macrophages accelerate atherosclerosis through miR-21-3p/PTEN-mediated VSMC migration and proliferation

“…The possible mRNA targets of miR-21-3p were predicted by TargetScan, miRWalk and miRbase. Among all candidate mRNAs, PTEN has been studied in the context of VSMC migration and proliferation 40-42. Dual-luciferase assay was performed to confirm whether miR-21-3p can bind to the predicted binding site in the PTEN 3'UTR.…”

Living Without a Pulse

“…However, the median duration of CF-LVAD support was only 263 days and the patients received a variety of different types of both pulsatile and continuous flow devices with varying implant configurations. By contrast, preliminary results from our lab suggest that CF-LVAD support may be associated with coronary artery remodeling and fibrosis 41, 42 . In normal physiology, coronary filling occurs predominantly in diastole when left ventricular pressures are lower and the coronary arteries are more dilated.…”

“…Contributors to increased afterload with CF-LVAD include a hyperadrenergic state with excess sympathetic tone, increased flow throughout the entirety of the cardiac cycle (including diastole), raising mean arterial pressures, and aortic stiffening with an upward/leftward shift in the aortic stress-strain curve. Another contributing factor to the low rate of myocardial recovery may be the structural changes within the coronary arteries that occur with CF-LVADs 41, 42 . If coronary flow reserve is restricted as a result of fibrotic changes within the vessels, this may result in insufficient myocardial oxygen supply for increased demands when the CF-LVAD is turned down or explanted.…”

Nicotinate-curcumin inhibits AngII-induced vascular smooth muscle cell phenotype switching by upregulating Daxx expression

“…The present findings showed that Daxx overexpression reversed the increase in expression of the synthetic phenotype marker OPN induced by AngII. Moulton et al have reported that a deficiency of PTEN (an essential regulator of differentiated VSMCs) promotes VSMC dedifferentiation and pathological vascular remodeling in human coronary arteries [ 25 ]. The highly proliferative growth phenotype expressed in VSMCs is driven by constitutive Akt expression and actively repressed by PTEN [ 26 ].…”