Comparative physiology of hypoxic pulmonary hypertension: historical clues from brisket disease

Some of the most valuable contributions to science have come about serendipitously, and, in 1913, when George Glover and Issac Newsom were commissioned by Colorado cattle ranchers to study high mountain disease, there was no way to anticipate the tremendous impact they would have on the study of high-altitude cardiopulmonary physiology. It was through the study of this agricultural malady that the correlation between chronic hypoxia, pulmonary hypertension, medial hypertrophy of the small pulmonary arteries, and right ventricular (RV) hypertrophy was recognized. The amount of vascular smooth muscle comprising the medial layer of pulmonary arteries varies significantly across species and can be used to predict the magnitude of pulmonary hypertension and RV hypertrophy elicited in response to chronic hypoxia. Within species, age and gender both significantly influence the severity of chronic hypoxic pulmonary hypertension and RV hypertrophy. However, despite all that we now know about hypoxic pulmonary hypertension, the specific mechanism(s) that differentiate the hypo- from the hyperresponder have yet to be elucidated. Adventitial fibroblast differentiation, circulating vascular progenitor cells, the presence or absence of specific vascular smooth muscle phenotypes, the upregulation or downregulation of vasoactive mediators, splice variants of oxygen-sensitive transcription factors, upregulation of growth factors, Ca(2+) sensitization, and/or the Rho/Rho-kinases signaling cascade could all potentially play a role in determining the extent of the vascular response to hypoxia within a species. Understanding the mechanisms that determine why some people, as well as some animals, exhibit a marked susceptibility to hypoxia is an important endeavor with far-reaching implications.