a component of the vascular remodeling and muscularization seen in pulmonary hypertensive states. Mural vascular changes and narrowing of the vascular lumen increase the resistance to blood flow (2). In animal models of pulmonary hypertension, various drugs have been shown to attenuate pulmonary vascular remodeling (Table I) (1). Exogenous heparin markedly inhibits smooth muscle cell proliferation in vivo after arterial injury and pulmonary vascular remodeling caused by hypoxia (2). Heparin

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... bits the development of pulmonary hypertension and vascular remodeling associated with prolonged hypoxia; however, the mechanism is not completely understood. Continuous heparin infusion for hypoxic exposure has been shown to attenuate increases in pulmonary arterial pressure, right ventricular hypertrophy, and pulmonary vascular remodeling in mice. Experimental studies have shown that heparin infusion decreases the severity of hypoxia-induced vascular changes, presumably by decreasing smooth muscle hyperplasia, by an effect related to that of the sodium-hydrogen antiporter (4). Heparin inhibits the increased Na + /H + exchange and the intracellular alcalinization (mediated by increased Na + /H + exchange) essential to proliferation (2). Heparin induces production of p21, a potent inhibitor of cyclindependent kinases, thereby potentially identifying a fundamental mechanism by which heparin inhibits proliferation in smooth muscle-like cells. Heparin maintains lung pericytes in the G 0 / G 1 growth phase (2). In the G 1 phase, p21 is a potent inhibitor of cyclin dependent protein kinases that are the principle regulatory proteins of cell cycle (2). Other possible mechanisms are; inhibition of the action of 5-HT and/or activation of MAPK kinase-1 (1). On the other hand, gycosaminoglycans such as heparin sulphate that are structurally related to heparin are part of the extra cellular matrix and known to regulate cell growth. Heparin at low concentration (0.03, 0.3-1.0 micrograms/ml) stimulates proliferation of normal human lung fibroblasts in culture whereas a higher concentration (100 micrograms/ml) has an inhibitory effect (5). Pulmonary vascular remodeling remains a big problem for various diseases seen in infancy. In animal models of pulmonary hypertension, administration of heparin has been shown to attenuate pulmonary vascular remodeling (1). Heparinlike molecules are thought to be therapeutically beneficial in pulmonary hypertension (2). Although it is used for its anticoagulant effect during ECMO, the anti-pulmonary vascular remodeling effect of heparin may also play a role for the recovery of ECMO patients. The anti-remodeling effect of heparin is not related to its anticoagulant properties (1). Pulmonary vascular remodeling in pulmonary hypertension is a complex, multi factorial process that occurs with many of the physical and chemical stimuli, including shear stress, stretch and hypoxia. Structural alterations extend to the periphery of the vascular tree and includes thickening of all three layers of the blood vessel wall (adventitia, media, intima) down to the precapillary vessels. Muscularisation involves both hypertrophy and hyperplasia of smooth muscle cells, as well as increased deposition of extra cellular matrix components. Additionally, proliferation, differentiation, and migration of smooth muscle precursor cells such as pericytes and fibroblasts may contribute to this phenomenon. Exposure of most animals to low levels of oxygen results in alveolar hypoxia and reliably causes chronic pulmonary hypertension and morphological alterations of the precapillary pulmonary vessels. Chronic hypoxic exposure of animals has been used for decades to induce pulmonary vascular remodeling. Piglets exposed to 3 days of hypoxia developed significant pulmonary hypertension and increased pulmonary vessel wall thickness with increased concentration of myofilaments within in the smooth muscle cells whereas further exposure to hypoxia for 14 days did not enhance the increase in pulmonary artery pressure and percentage wall thickness (3). The proliferation of pericytes (smooth muscle-like cells) found in the distal pulmonary arterial microvasculature is believed to be