Hypoxic pulmonary vasoconstriction (HPV) diverts blood flow away from the lung during in utero development and it helps to optimize lung gas exchange after birth by contributing to the matching of blood flow and ventilation. While the characteristics of HPV have been well described, the underlying mechanism of O2 sensing is not established. Previous studies from this lab have implicated mitochondria in the O2 sensing underlying other responses to hypoxia in hepatocytes and cardiac myocytes. The generation of reactive oxygen species (ROS) by mitochondria in response to low PO2 could represent an O2- dependent oxidant signal during physiological hypoxia. The ability of mitochondria to generate ROS during hypoxia in diverse cell types led us to hypothesize that a similar process may underlie HPV in the lung. The primary focus of this research is to investigate the role of mitochondria as the oxygen sensor underlying the HPV response. Preliminary data developed in the isolated, perfused rat lung has shown that selective mitochondrial inhibitors and antioxidants can selectively attenuate HPV. This work provides strong justification for this proposal, which will extend those findings in studies designed to more critically evaluate the role of the mitochondria and ROS in the HPV response in isolated pulmonary myocytes. Interventions with site-specific mitochondrial inhibitors and antioxidants will help to evaluate the role of the mitochondria and ROS generation in the HPV response. The generation of a respiration-deficient pulmonary myocyte cell line and the over-expression of catalase through transfection will further test our hypothesized mechanism underlying the HPV response. If successful, these studies could provide important and novel insight into the mechanism of O2 sensing in HPV, and potentially add understanding of factors that initiate remodeling of the pulmonary circulation during chronic hypoxia. The cell and molecular approaches I will acquire will also enhance my development as an investigator.
| Waypa, Gregory B; Schumacker, Paul T (2002) O(2) sensing in hypoxic pulmonary vasoconstriction: the mitochondrial door re-opens. Respir Physiol Neurobiol 132:81-91 |
| Waypa, Gregory B; Marks, Jeremy D; Mack, Mathew M et al. (2002) Mitochondrial reactive oxygen species trigger calcium increases during hypoxia in pulmonary arterial myocytes. Circ Res 91:719-26 |
| Waypa, G B; Chandel, N S; Schumacker, P T (2001) Model for hypoxic pulmonary vasoconstriction involving mitochondrial oxygen sensing. Circ Res 88:1259-66 |
