Grant: Operating Grant

In the lung, blood vessels react to hypoxia with a rapid and sustained contraction termed hypoxic pulmonary vasoconstriction (HPV). HPV redistributes blood flow from areas which are poorly aerated to intact lung regions with better ventilation. In this way, sufficient blood oxygenation is maintained even when 50% of lung tissue no longer contribute to gas exchange. Lung inflammation or sepsis, but also commonly used anesthetics attenuate HPV and may thus impair blood oxygenation. A perpetuated HPV may also be detrimental in generalized hypoxia e.g. at high altitude, since contraction of all resistance vessels will increase blood pressure in the lung and ultimately cause lung edema and/or right heart failure. Despite its relevance, the involved signaling mechanisms and the exact sites of oxygen sensing and vasoconstriction are incompletely understood. We have established innovative imaging methods which allow for the direct visualization of blood vessels and blood oxygenation in the intact lung. We can show that the primary site of gas exchange is at the level of the smallest blood vessels, the capillaries, while vasoconstriction is confined to upstream arterioles. We thus postulate a signal conduction mechanism which must propagate the hypoxic signal from the capillaries to the arterioles and suggest a critical role for the molecule connexin 40 (Cx40) which facilitates rapid signal conduction by electric coupling of adjoining cells. Our proposed experiments aim to (i) characterize the role of Cx40 in HPV, (ii) identify the cellular mechanisms which underlie the signal conduction from capillaries to arterioles, and (iii) test the relevance of this concept for clinical conditions in which HPV is impaired or perpetuated. The results of this project will change our understanding of one of the basic mechanisms of vascular regulation, and will provide the basis for new therapeutic strategies in the treatment of diseases in which lung vascular tone is dysregulated.