OXYGEN SENSING IN VASCULAR SMOOTH MUSCLE: AN INVESTIGATION OF MECHANISMS IMPORTANT FOR HYPOXIA-INDUCED VASODILATION IN PORCINE CORONARY ARTERY
Abstract (Summary)In large coronary arteries the physiological response to a decrease in oxygen tension (hypoxia) is vasodilation, increasing blood flow to the heart. The mechanism(s) underlying hypoxia-induced vasorelaxation remains elusive. Our laboratory has previously investigated prevailing theories of oxygen sensing in the porcine coronary artery (Circ. Research 86:862-870, 2000). In that study we examined the effects of hypoxia on isometric force, intracellular Ca ^2+ , pH, and energetics. None of these theories applied in the porcine coronary artery. In addition, the specific blockade of various ion channels did not affect the relaxation response to acute hypoxia. We observed an unperturbed hypoxia-induced relaxation in the presence of K ATP , K Ca , and K IR inhibition as well as during inhibition of protein kinase G and C activity. This suggested that there is a novel mechanism of hypoxic relaxation in this tissue not explained by the current theories. However, we did observe relaxation to hypoxia with and without changes in intracellular Ca ^2+ . We describe this as Ca ^2+ -dependent and -independent mechanisms of hypoxic relaxation. We discovered that organ culture at 37 (C for 24 hr specifically inhibits relaxation to hypoxia in porcine coronary without significantly affecting isometric force generation. I utilize this organ culture model to identify changes in other pathways that could be involved in hypoxia-induced relaxation. Both Ca ^2+ -dependent and -independent mechanisms of hypoxic relaxation are inhibited by organ culture, but A- and G-kinase relaxation pathways remain intact. This suggests that inhibition by organ culture is specific to hypoxic relaxation and is a novel tool for investigating mechanisms of oxygen sensing. I also examined changes in gene and protein expression after organ culture using differential display and proteomics. Results indicate a possible role for voltage-dependent K ^+ channels and ryanodine receptors in the Ca ^2+ -dependent component of hypoxic relaxation. Additionally, I identify changes smooth muscle protein expression following organ culture that could contribute to an inhibition of hypoxic relaxation and have a role in the Ca ^2+ -independent component. Thus, organ culture offers a unique approach to elucidate the mechanism of hypoxic relaxation. Together these results offer new unique targets for the mechanism of hypoxia-induced vasodilation in the porcine coronary artery.
School:University of Cincinnati
School Location:USA - Ohio
Source Type:Master's Thesis
Date of Publication:01/01/2002