Heparin-like molecules inhibit pulmonary vascular pericyte proliferation in vitro.
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 G(0)/G(1) 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.
Division of Cardiology and Lady Davis Institute for Medical Research, Sir Mortimer B. Davis Jewish General Hospital, McGill University, Montreal, Quebec, Canada H3T 1E2.
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Khoury
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Langleben
D000584:Amiloride / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001485:Basement Membrane / Q000378:metabolism; D015153:Blotting, Western; D002453:Cell Cycle / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000096:biosynthesis; D004305:Dose-Response Relationship, Drug; D006025:Glycosaminoglycans / Q000494:pharmacology; D019812:Heparan Sulfate Proteoglycans / Q000494:pharmacology; D006493:Heparin / Q000031:analogs & derivatives / Q000494:pharmacology*; D008168:Lung / Q000098:blood supply*; D008297:Male; D008833:Microcirculation / Q000166:cytology / Q000187:drug effects; D020286:Pericytes / Q000166:cytology* / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects; D017923:Sodium-Hydrogen Exchangers / Q000037:antagonists & inhibitors
C493958:Cdkn1a protein, rat; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D006025:Glycosaminoglycans; D019812:Heparan Sulfate Proteoglycans; D017923:Sodium-Hydrogen Exchangers; C013786:A73025; C039465:5-dimethylamiloride; D000584:Amiloride; D006493:Heparin