Hypoxia induces cell-specific changes in gene expression in vascular wall cells: implications for pulmonary...

Mammals respond to reduced oxygen concentrations (hypoxia) in many different ways at the systemic, local, cellular and molecular levels. Within the pulmonary circulation, exposure to chronic hypoxia has been demonstrated to illicit increases in pulmonary artery pressure as well as dramatic structural changes in both large and small vessels. It has become increasingly clear that the response to hypoxia in vivo is differentially regulated at the level of specific cell types within the vessel wall. For instance, in large pulmonary blood vessels there is now convincing evidence to suggest that the medial layer is made up of many different subpopulations of smooth muscle cells. In response to hypoxia there are remarkable differences in the proliferative and matrix producing responses of these cells to the hypoxic environment. Some cell populations proliferate and increase matrix protein synthesis, while in other cell populations no apparent change in the proliferative or differentiation state of the cell takes place. In more peripheral vessels, the predominant proliferative changes in response to hypoxia in the pulmonary circulation occur in the adventitial layer rather than in the medial layer. Here again, specific increases in proliferation and matrix protein synthesis take place. Accumulating evidence suggests that the unique responses exhibited by specific cell types of hypoxia in vivo can be modeled in vitro. We have isolated, in culture, specific medial cell populations which demonstrate significant increases in proliferation in response to hypoxia, and others which exhibit no change or, in fact, a decrease in proliferation under hypoxic conditions. We have also isolated and cloned several unique populations of adventitial fibroblasts. There is good evidence that only certain fibroblast populations are capable of responding to hypoxia with an increase in proliferation. We have begun to elucidate the signaling pathways which are activated in those cell populations that exhibit proliferative responses to hypoxia. We show that hypoxia, in the absence of serum or mitogens, specifically activates select members of the protein kinase C isozyme family, as well as members of the mitogen-activated protein kinase (MAPK) family of proteins. This selective activation appears to take place in response to hypoxia only in those cells exhibiting a proliferative response, and antagonists of this pathway inhibit the response. Thus, there appear to be cells within each organ that demonstrate unique responses to hypoxia. A better understanding of why these cells exist and how they specifically transduce hypoxia-mediated signals will lead to a better understanding of how the changes in the pulmonary circulation take place under conditions of chronic hypoxia.