Factors regulating arteriolar tone during microvascular growth

Abstract

Growth of the arteriolar network is accompanied by progressive changes in pressure and flow, and in the metabolic environment to which the arterioles are exposed. This dissertation was carried out to investigate the extent to which mechanisms involved in local blood flow regulation may also change during this growth. We isolated gracilis muscle arterioles from weanling (age 25-26 days) and juvenile (44-66 days) rats, and studied the responsiveness of these vessels to both myogenic and endothelium-dependent stimuli. Overall arteriolar responses to the endothelium-dependent agonists acetylcholine (ACh), A23187, VEGF and simvastatin were not different between age groups. Responses of juvenile arterioles to ACh and simvastatin were significantly reduced by inhibition of nitric oxide synthase or cyclooxygenase, by the hydrogen peroxide scavenger catalase, and by potassium channel inhibition. Responses of weanling arterioles to ACh and simvastatin were unaffected by these treatments, but significantly reduced by heme oxygenase inhibition. Arteriolar growth during juvenile maturation is accompanied by an increase in myogenic responsiveness, possibly because endotheliumderived PGH 2 or TXA 2 assumes a role in reinforcing myogenic activity over this period. In conclusion, mediators of endothelium-dependent dilation change during growth, with carbon monoxide contributing largely to these responses in young animals, and a combination of nitric oxide, prostanoids and hydrogen peroxide contributing to these responses in older animals. These data suggest that age-dependent differences in the control of vascular tone exist and may have significant implications for the regulation of tissue perfusion. DEDICATION I would like to dedicate this work to my parents, Pamela and Patrick Balch, who have offered unwavering encouragement and support, instilled in me the self-confidence to fulfill my dreams, and who have stood by my side through every decision, accomplishment, and failure. I love you both so much. Thanks for being the amazing parents you are. iii Jefferson C. Frisbee for their support and faith in my abilities. They have been a great team-two completely different personalities and research interests, but both providing extremely valuable insight and support. Wherever they may have differed in their overall objectives for me, they were always cooperative and accommodating, and had my best interests in mind. Dr. Frisbee-you have an intense ambition and motivation that inspire and amaze me. Dr. Boegehold-I greatly appreciate all of your efforts during these last few months not only working with me to understand some difficult data and helping to get the last few manuscripts into shape, but also in assisting me with the completion of this work. As an aside, I hope I may someday become as skilled in the art of diplomacy as you! Thank you both for taking me under your wings. I have learned a great deal under your mentorship.