Heparin-like molecules inhibit pulmonary vascular pericyte proliferation in vitro

Proliferation of vascular pericytes (PCs), smooth muscle-like cells found i n the distal microvasculature, contributes to vascular remodeling in pulmon ary hypertension. The factors controlling lung PC quiescence in normal stat es are poorly understood. We demonstrate that exogenous heparin and heparan sulfate proteoglycans inhibit rat lung PC proliferation in vitro as does p ulmonary vascular subendothelial matrix, particularly its heparan sulfate c omponent. Heparin inhibits the intracellular alkalinization essential to pr oliferation, and we show that inhibition of alkalinization by 5-(N,N-dimeth yl)amiloride also reduces PC proliferation. As shown by DNA staining and fl uorescence-activated cell sorting analysis, heparin does not induce apoptos is in PCs. However, heparin maintains lung PCs in the G(0)/G(1) growth phas e. Heparin induces production of p21, a potent inhibitor of cyclin-dependen t 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 microvascul ature. They also further support the rationale that heparin-like molecules might be therapeutically beneficial in pulmonary hypertension.