Proliferation of pulmonary endothelial cells (EC) is required for normal lung development and is involved in the pathogenesis of the vaso-occlusive plexiform lesions that complicate advanced pulmonary hypertension. The role of ion channels in regulating pulmonary EC cell cycle has not been fully elucidated. Recently, volume-regulated anion channels (VRAC) have been implicated in modulating angiogenesis. These channels are classically associated with the current activated by cell swelling (Icswell). We provide evidence that the EC mitogen VEGF activates VRAC, swelling and VEGF activate distinct signaling pathways, and blockade of VRAC completely inhibits proliferation of human pulmonary microvascular EC (HPMVEC). Based on this information we hypothesize: Activation of VRAC is a critical step in mitogenic stimulation of pulmonary endothelial cells, Divergent signaling pathways activated by endothelial cell swelling or mitogens result in tmique patterns of gene activation and Acute and chronic hypoxia activate VRAC and gene expression utilizing similar signaling pathways to cell swelling and mitogens, respectively. We propose three specific aims: 1) Test the hypothesis in human PMVEC that while mitogens and cell swelling both activate VRAC, distinct upstream signaling pathways link the stimuli to channel activation. 2) Test the hypothesis that mitogens and cell swelling activate unique patterns of gene expression dependent both on activation of VRAC and the distinct signaling pathways associated with VRAC activation. 3) Test the hypothesis that acute and chronic hypoxia act via mechanisms similar to cell swelling and mitogens, respectively. Upon completion of our studies we anticipate having more fully defined the role of VRAC and associated signaling pathways in regulation of pulmonary endothelial cell proliferation; work we anticipate will provide important clues to the pathogenesis of pulmonary vascular disease.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL014985-35
Application #
7371911
Study Section
Project Start
2007-04-01
Project End
2008-03-31
Budget Start
2007-04-01
Budget End
2008-03-31
Support Year
35
Fiscal Year
2007
Total Cost
$411,367
Indirect Cost
Name
University of Colorado Denver
Department
Type
DUNS #
041096314
City
Aurora
State
CO
Country
United States
Zip Code
80045
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