Abnormal vascular smooth muscle cell (VSMC) proliferation is a key feature of vascular diseases such as pulmonary hypertension and atherosclerosis. Increased VSMC growth under hypoxia is the result of complex feedback loop mechanisms acting on the vessel wall. Hypoxia increases the expression of the heme oxygenase-1 (HO-1) gene by VSMC. HO-1 catalyzes the breakdown of heme leading to the formation of the vasodilator CO and the antioxidant, bilirubin. Like NO, CO activates guanylyl cyclase resulting in elevated cGMP levels which in turn cause VSMC relaxation and limit VSMC proliferation. Our data show that it is the increase in CO by VSMC that (1) inhibits the hypoxic induction of the endothelial cell-derived mitogens, endothelin and platelet derived growth factor-B, indirectly inhibiting VSMC proliferation; (2) that CO also suppresses VSMC proliferation independent of endothelial cells by inhibiting the expression of E2F-1, a cell cycle-specific transcription factor; and (3) inhibits the trans-activating function of hypoxia-inducible factor-1 on gene expression by hypoxia. Based on these observations, we hypothesize that VSMC-derived CO is a physiologic regulator of vascular homeostasis. For this reason, we have created and propose to use transgenic mice with conditional, organ-specific expression of HO-1 to study the physiology of this important molecule. Our long-term objective is to understand how CO modulates endothelial-VSMC interactions under physiologic and pathophysiologic conditions of hypoxia to provide the basis of novel therapeutic strategies for the treatment of vascular disorders such as pulmonary hypertension and atherosclerosis. We propose the following specific aims: (1) To investigate the molecular mechanisms of hypoxic gene regulation by CO. (2) To define the role of CO in the maintenance of pulmonary vascular homeostasis. (3) To define the role of HO-1 in vascular injury.
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