Selective Inactivation of PTEN in Smooth Muscle Cells Synergizes With Hypoxia to Induce Severe Pulmonary Hypertension

Abstract

BackgroundPulmonary vascular remodeling in pulmonary hypertension (PH) is characterized by increased vascular smooth muscle cell (SMC) and adventitial fibroblast proliferation, small vessel occlusion, and inflammatory cell accumulation. The underlying molecular mechanisms driving progression remain poorly defined. We have focused on loss of the phosphatase PTEN in SMCs as a major driver of pathological vascular remodeling. Our goal was to define the role of PTEN in human PH and in hypoxia‐induced PH using a mouse model with inducible deletion of PTEN in SMCs.Methods and ResultsStaining of human biopsies demonstrated enhanced inactive PTEN selectively in the media from hypertensive patients compared to controls. Mice with induced deletion of PTEN in SMCs were exposed to normoxia or hypoxia for up to 4 weeks. Under normoxia, SMC PTEN depletion was sufficient to induce features of PH similar to those observed in wild‐type mice exposed to chronic hypoxia. Under hypoxia, PTEN depletion promoted an irreversible progression of PH characterized by increased pressure, extensive pulmonary vascular remodeling, formation of complex vascular lesions, and increased macrophage accumulation associated with synergistic increases in proinflammatory cytokines and proliferation of both SMCs and nonSMCs.ConclusionsChronic inactivation of PTEN selectively in SMC represents a critical mediator of PH progression, leading to cell autonomous events and increased production of factors correlated to proliferation and recruitment of adventitial and inflammatory cells, resulting in irreversible progression of the disease.

Deficiency of Akt1, but not Akt2, attenuates the development of pulmonary hypertension

“…PTEN is an upstream phosphatase that prevents activation of Akt indirectly, and previous work has shown that inactivated PTEN is associated with pulmonary hypertension in humans as well as increased severity of HPH in animal models (19). Our TG PTEN mice have previously been demonstrated to have significantly upregulated PTEN gene and protein expression, which can prevent Akt phosphorylation (11).…”

“…Inhibition of the Akt/mTOR signaling cascade by phosphatase and tensin homolog deleted on chromosome 10 (PTEN) (a phosphatase that converts phosphatidylinositol 4,5-trisphosphate to phosphatidylinositol 4,5-bisphosphate, inhibiting Akt phosphorylation), rapamycin (which blocks mTOR), or Akt inhibition (specific inhibitors that bind to Akt to prevent its phosphorylation), has been well demonstrated to attenuate cell proliferation in cancer cells (64), embryonic stem cells (2,61), vascular progenitor cells (25,27), coronary arterial smooth muscle cells (9,14), and PASMC (19,20,29,49). Our previous work has also demonstrated the importance of the Akt/mTOR pathway in both thrombin-and PDGF-induced enhancement of store-operated Ca 2ϩ entry (SOCE) and cell proliferation in PASMC (44,45), whereas downregulation of transient receptor potential canonical (TRPC) channels reduced SOCE and significantly inhibit PASMC proliferation and migration (59,72).…”

“…Blockade of the Akt/mTOR signaling with rapamycin or an Akt inhibitor can significantly attenuate PASMC proliferation (20). Deletion of PTEN in mouse smooth muscle cells results in vascular remodeling (43), and exposure of PTEN conditional knockout (KO) mice to hypoxia causes severe pulmonary hypertension (19). These studies show the crucial roles of PTEN in the development and progression of pulmonary vascular disease.…”

Transforming growth factor-beta1 upregulation triggers pulmonary artery smooth muscle cell proliferation and apoptosis imbalance in rats with hypoxic pulmonary hypertension via the PTEN/AKT pathways

“…Previous studies have documented that hypoxia increases the levels of TGFβ1 and down-regulates PTEN expression in PAH induced by monocrotaline or exposure to hypoxia (Horita, Furgeson, 2013, Ostriker, Horita, 2014. Since both TGFβ1 and PTEN are key molecules in vascular responses to hypoxic remodeling, it is necessary to understand whether there is an interplay between the TGFβ1 and PTEN.…”

Axis inhibition protein 2 deficiency leads to hypoxic pulmonary hypertension through β-catenin signaling pathway

“…Blocking this oncogenic signature led to decreased PAH-pulmonary arterial smooth muscle cell (PASMC) proliferation and increased apoptosis in PASMC cells [9]. Phosphataseand-tensin homolog on chromosome 10, a tumor suppressor gene involved in regulating cell division, migration, and angiogenesis were recently implicated in the regulation of pulmonary vascular resistance and development of PAH [10].…”