Hyperproliferative apoptosis-resistant endothelial cells in idiopathic pulmonary arterial hypertension.

  title={Hyperproliferative apoptosis-resistant endothelial cells in idiopathic pulmonary arterial hypertension.},
  author={Fares A. Masri and Weiling Xu and Suzy A. Comhair and Kewal Asosingh and Michelle Koo and Amit Vasanji and Judith A. Drazba and Bela Anand-Apte and Serpil C Erzurum},
  journal={American journal of physiology. Lung cellular and molecular physiology},
  volume={293 3},
  • F. MasriWeiling Xu S. Erzurum
  • Published 1 September 2007
  • Biology, Medicine
  • American journal of physiology. Lung cellular and molecular physiology
Idiopathic pulmonary arterial hypertension (IPAH) is characterized by plexiform vascular lesions, which are hypothesized to arise from deregulated growth of pulmonary artery endothelial cells (PAEC). Here, functional and molecular differences among PAEC derived from IPAH and control human lungs were evaluated. Compared with control cells, IPAH PAEC had greater cell numbers in response to growth factors in culture due to increased proliferation as determined by bromodeoxyuridine incorporation… 

Figures and Tables from this paper

Notch1 signalling regulates endothelial proliferation and apoptosis in pulmonary arterial hypertension

It is concluded that Notch1 plays a critical role in PAH and Notch inhibitors may be a promising therapeutic option for PAH.

Autocrine fibroblast growth factor-2 signaling contributes to altered endothelial phenotype in pulmonary hypertension.

The findings suggest that excessive autocrine release of endothelial-derived FGF2 in IPAH contributes to the acquisition and maintenance of an abnormal EC phenotype, enhancing proliferation through constitutive activation of ERK1/2 and decreasing apoptosis by increasing BCL2 and BCL-xL.

Evidence for cell fusion is absent in vascular lesions associated with pulmonary arterial hypertension.

  • S. MajkaM. Skokan J. West
  • Biology, Medicine
    American journal of physiology. Lung cellular and molecular physiology
  • 2008
Analysis of CD45/CD133 localization, cell fusion, and proliferation during late-stage PAH in human lung tissue from control subjects and subjects with idiopathic (IPAH) and familial (FPAH) PAH suggest that abnormal lesion formation in PAH occurs in the absence of cell fusion.

Suppression of endothelial CD39/ENTPD1 is associated with pulmonary vascular remodeling in pulmonary arterial hypertension.

Sustained attenuation of CD39 activity through ATP accumulation is tightly linked to vascular dysfunction and remodeling in PAH and could represent a novel target for therapy.

Vascular pathobiology of pulmonary hypertension

Endothelial Apoptosis in Pulmonary Hypertension Is Controlled by a microRNA/Programmed Cell Death 4/Caspase-3 Axis

Findings support the existence of a microRNA-21–responsive PDCD4/caspase-3 pathway in the pulmonary tissues that when active serves to promote endothelial apoptosis in vitro and PH in vivo.

Evidence of dysfunction of endothelial progenitors in pulmonary arterial hypertension.

Evidence is provided of the involvement of progenitor cells in the vascular remodeling associated with PAH, and Dysfunction of circulating progenitors in PAH may contribute to this process.

Endothelial cell energy metabolism, proliferation, and apoptosis in pulmonary hypertension.

The phenotypic changes of the endothelium in PAH are reviewed and the biochemical mechanisms accounting for the proliferative, glycolytic, and strongly proangiogenic phenotype of these dysfunctional cells are reviewed, which consequently foster the panvascular progressive pulmonary remodeling inPAH.

Circulating angiogenic precursors in idiopathic pulmonary arterial hypertension.

Vascular remodeling in idiopathic pulmonary arterial hypertension (IPAH) involves hyperproliferative and apoptosis-resistant pulmonary artery endothelial cells. In this study, we evaluated the

Dehydroepiandrosterone inhibits the Src/STAT3 constitutive activation in pulmonary arterial hypertension.

DHEA reverses pulmonary hypertension in part by inhibiting the Src/STAT3 axis inhibition and improves experimental PAH (monocrotaline rats) by decreasing mean PA pressure and right ventricle hypertrophy.



Initial apoptosis is followed by increased proliferation of apoptosis‐resistant endothelial cells

Endothelial cell death resulted in the selection of an apoptosis‐resistant, proliferating phenotypically altered endothelial cell phenotype.

Inhibition of the VEGF receptor 2 combined with chronic hypoxia causes cell death‐dependent pulmonary endothelial cell proliferation and severe pulmonary hypertension

It is demonstrated here that VEGFR‐2 blockade with SU5416 in combination with chronic hypobaric hypoxia causes severe pulmonary hypertension associated with precapillary arterial occlusion by proliferating endothelial cells.

Monoclonal endothelial cell proliferation is present in primary but not secondary pulmonary hypertension.

The data of a frequent monoclonal endothelial cell proliferation in PPH suggests that a somatic genetic alteration similar to that present in neoplastic processes may be responsible for the pathogenesis of PPH.

Inhibition of STAT3 prevents neointima formation by inhibiting proliferation and promoting apoptosis of neointimal smooth muscle cells.

The STAT3-mediated pathway plays an important role in neointima formation through enhanced vascular SMC accumulation by promoting cell proliferation and survival in cultured vascular smooth muscle cells.

Exuberant endothelial cell growth and elements of inflammation are present in plexiform lesions of pulmonary hypertension.

Immunohistochemical evidence and Morphologically and immunohistochemically, the lesions resembled the neovascularization associated with the brain tumor glioblastoma multiform and the presence of perivascular inflammatory cells suggested that cytokines and growth factors may further influence the development of the plexiform lesion.

Vascular Endothelial Growth Factor Induces Expression of the Antiapoptotic Proteins Bcl-2 and A1 in Vascular Endothelial Cells*

Findings indicate that Bcl-2 plays an important role in mediating the survival activity of VEGF on endothelial cells, and overexpression of B cl-2 by means of transient biolistic transfection experiments of HUVE cells was sufficient to prevent endothelial Cells from apoptotic cell death in the absence of V EGF.

Primary Pulmonary Hypertension Is Associated With Reduced Pulmonary Vascular Expression of Type II Bone Morphogenetic Protein Receptor

The cellular localization of BM PR-II is consistent with a role in the formation of pulmonary vascular lesions in PPH, and reduced BMPR-II expression may contribute to the process of vascular obliteration in severe pulmonary hypertension.

Peroxisome Proliferator-Activated Receptor Gamma (PPAR&ggr;) Expression Is Decreased in Pulmonary Hypertension and Affects Endothelial Cell Growth

It is concluded that fluid shear stress decreases the expression of PPAR&ggr; in endothelial cells and that loss of PPARI; expression characterizes an abnormal, proliferating, apoptosis-resistant endothelial cell phenotype.

Serine phosphorylation of STAT3 is essential for Mcl-1 expression and macrophage survival.

The present study focused on the role of signal transducer and activator of transcription 3 (STAT3) in regulation of Mcl-1 in macrophages and demonstrated that the STAT3-mediated expression of M cl-1 is essential for the survival of primary human in vitro differentiated macrophaging.

Nuclear Translocation of Phosphorylated STAT3 Is Essential for Vascular Endothelial Growth Factor-induced Human Dermal Microvascular Endothelial Cell Migration and Tube Formation*

Analysis of the role of STAT3 in the migration and tube formation of the human dermal microvascular endothelial cells (HDMEC) and a dominant-negative STAT3 using adenovirus vector system demonstrate that STAT3 and its phosphorylation are involved in the downstream pathway of V EGF/VEGFR interaction and regulate VEGF-induced HDMEC migration andtube formation.