University of Giessen Lung Center

Vasoconstriction and chronic vascular remodeling induced by hypoxia in the pulmonary vasculature

Acute, prolonged and chronic alveolar hypoxia

The vascular effects that are induced by alveolar hypoxia can be separated into three phases. The first, acute phase (after a duration of hypoxia between several seconds to several minutes) induces a fully reversible vasoconstrictor response that adapts blood perfusion to alveolar ventilation, and thus optimizes pulmonary gas exchange (hypoxic pulmonary vasoconstriction = HPV = von Euler-Liljestrand-mechanism). A disturbance in HPV may result in life-threatening hypoxemia. The second, prolonged phase (minutes to hours) induces an acute, partially reversible, increase in vascular resistance, which leads to the effects of chronic hypoxia. The third, chronic phase (days to weeks to years) induces the development of a chronic vascular remodeling process characterized by media hypertrophy and smooth muscle cell proliferation. Both the continuous activation of HPV as well as the activation of the proliferative processes in chronic hypoxia then result in pulmonary hypertension.

We aim to identify the oxygen sensing and signal transduction processes underlying the three phases in different models of hypoxia. Apart from pharmacological and molecular strategies, this includes investigations in a variety of transgenic mice.

Candidate pathways that have been in the focus of my research group for many years are investigated. Among these are:

• NADPH oxidases
• Reactive oxygen species Mitochondrial redox regulation and superoxide release
• K+, Ca2+-channels and Ca2+ homeostasis
• NO-guanylatcyclase-phosphodiesterase axis
• HIF-signaltransduction

Proteomic and genomic screenings are performed to identify new targets for interventional therapy in hypoxia-induced pulmonary hypertension.

The overall aim is to develop new strategies to antagonize vascular remodeling and to activate disturbed HPV.