Relationships between vascular oxygen sensing mechanisms and hypertensive disease processes.

Many pathological conditions, like sleep apnea (SA), preeclampsia, high altitude sickness, and chronic obstructive pulmonary disease, that cause intermittent or chronic hypoxia, are often associated with the development of either systemic or pulmonary hypertension. Mechanisms sensing hypoxia may be important contributors to the development of pulmonary hypertension and to tissue injury and repair associated with hypertensive disease and in integrated aspects of cardiovascular function. This review will focus on highlighting how some of the better documented oxygensensing mechanisms associated with vascular regulation could be influenced by poorly understood interactions between hypoxia and hypertension. It will also consider some of the identified integrated interactions between hypoxia and hypertensive disease processes that could contribute to the progression of disease processes, such as renal hypertension. High altitude and chronic obstructive pulmonary disease are thought to promote pulmonary hypertension by exposing the pulmonary circulation to chronic hypoxia as a result of the low partial pressure of oxygen at high altitude and increases in the diffusion distance for oxygen, respectively. Although high altitude can initially promote increased systemic blood pressure, this change appears to reverse with time. Interestingly, hypobaric hypoxia conditions of high altitude were observed to prevent the development of hypertension and skeletal muscle arteriolar rarefaction in spontaneously hypertensive rats. Living at high altitude seems to lower blood pressure only in children, and it did not appear to attenuate hypertension in obese adults consuming high-fat diets. Based on studies in animal models of acute and chronic hypoxia, hypoxic pulmonary vasoconstriction (HPV) is initially activated. Eventually endothelial dysfunction associated with a loss of NO and increased reactive oxygen species (ROS), endothelin, serotonin, and contractile prostaglandins contribute to maintaining elevated pulmonary artery pressure through increased intracellular Ca levels and rho kinaseassociated myofilament Ca sensitivity. Although the mechanisms involved in PO2 sensing and eliciting constriction are incompletely understood, there is consensus that hypoxia-evoked redox and ROS changes play a significant role in HPV and pulmonary hypertension development. Other than vasoconstriction, remodeling of pulmonary arteries also has a significant role in increasing pulmonary arterial pressure. Numerous studies are ongoing to identify inflammatory and progenitor cell mechanisms involved in muscularization of resistance arteries, as well as adventitial fibroblast-promoted matrix remodeling and neointimal plexiform lesion formation. The emerging picture from these studies suggests that ROS and oxidant-associated redox signaling through mechanisms including hypoxia-inducible factor (HIF) and rho kinase could be promoting the remodeling that aggravates hypertension. Interestingly, therapies promoting guanylate cyclase activation under oxidant conditions or preventing cGMP degradation by treatment with sildenafil seem to be beneficial in attenuating many aspects of pulmonary hypertensive disease processes. The function of signaling mechanisms associated with HPV are thought to be important factors in modulating pulmonary hypertension development.