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Am J Physiol Lung Cell Mol Physiol 279: L252-L261, 2000;
1040-0605/00 $5.00
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Vol. 279, Issue 2, L252-L261, August 2000

Heparin-like molecules inhibit pulmonary vascular pericyte proliferation in vitro

Joseph Khoury and David Langleben

Division of Cardiology and Lady Davis Institute for Medical Research, Sir Mortimer B. Davis Jewish General Hospital, McGill University, Montreal, Quebec, Canada H3T 1E2

Proliferation of vascular pericytes (PCs), smooth muscle-like cells found in the distal microvasculature, contributes to vascular remodeling in pulmonary hypertension. The factors controlling lung PC quiescence in normal states are poorly understood. We demonstrate that exogenous heparin and heparan sulfate proteoglycans inhibit rat lung PC proliferation in vitro as does pulmonary vascular subendothelial matrix, particularly its heparan sulfate component. Heparin inhibits the intracellular alkalinization essential to proliferation, and we show that inhibition of alkalinization by 5-(N,N-dimethyl)amiloride also reduces PC proliferation. As shown by DNA staining and fluorescence-activated cell sorting analysis, heparin does not induce apoptosis in PCs. However, heparin maintains lung PCs in the G0/G1 growth phase. Heparin induces production of p21, a potent inhibitor of cyclin-dependent kinases, thereby potentially identifying a fundamental mechanism by which heparin inhibits proliferation in smooth muscle-like cells. These studies establish additional similarities between lung PCs and smooth muscle cells and provide further understanding of growth control in the lung microvasculature. They also further support the rationale that heparin-like molecules might be therapeutically beneficial in pulmonary hypertension.

pulmonary hypertension; extracellular matrix; cell cycle; smooth muscle cell; proteoglycans


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