Angiopoietin-1 and Pulmonary Hypertension

Our very existence depends on the air that we breathe, as well as the remarkable systems that have evolved to ensure that the oxygen we take into our lungs is efficiently delivered to the rest of the body via the bloodstream. When these systems begin to fail, life itself can become quite tenuous. Such failure occurs in pulmonary hypertension, a rare but serious disease whose pathophysiology remains obscure and increasingly controversial, as highlighted by two recent studies.1,2 Both studies focus on the potential role of angiopoietin-1 in this disease, but reach entirely antithetical conclusions. The right side of the heart pumps blood into the lung vasculature, which consists of a low-resistance network that normally adjusts to increases in blood flow (eg, as necessitated by exercise) by dilation of its terminal arterioles to allow for increased flow without increasing resistance. In pulmonary hypertension, pulmonary arterial pressure is increased at rest and ratchets up dramatically with exercise, due to an inability to easily accommodate increased flow, imposing stress on the right ventricle. In response to the increased back pressure, the right side of the heart can hypertrophy to the point of failure. Current treatments are moderately effective at best. A study featured in this issue of Circulation Research,2 from the laboratory of Duncan Stewart, claims that angiopoietin-1 can have dramatic protective effects in an animal model of pulmonary hypertension. On the other hand, a recent article in the New England Journal of Medicine by Thistlethwaite and colleagues1 argues quite the opposite, based on examining angiopoietin-1 levels and activities in human patients, and instead suggests that angiopoietin-1 might be to blame for causing this disease. Why the two opposing perspectives? Evaluating the controversy requires some background on angiopoietin-1, as well as some insight into different views of what might be the cellular basis of this poorly understood disease. The number of growth factors that specifically act on the blood vasculature is quite small and are limited to two families of factors known by their prototypical members—the vascular endothelial growth factor (VEGF) family and the angiopoietin family.3–5 Members of these families achieve their specificity based on the limited distributions of their receptors, which are expressed almost exclusively on the vascular endothelium. Both families act primarily via receptor tyrosine kinases, with those for the VEGFs termed VEGFR1, VEGFR2, and VEGFR3, and those for the angiopoietins termed Tie1 and Tie2. The enormous interest in these two families of growth factors results from the realization that they evolved to play very specific and critical roles in the vasculature, as initially suggested by their receptor distributions, and more recently confirmed by genetic knockouts of these factors and their receptors.3–5 While VEGF was discovered more than two decades ago,4,6 angiopoietin-1 has been identified much more recently,7 and thus its biological, pathological, and potential therapeutic roles are less well understood. One major emerging theme is that the VEGFs and the angiopoietins are not redundant, but instead play distinct and complementary roles, with the VEGFs acting early to initiate vessel growth, and the angiopoietins acting subsequently to promote vessel maturation and maintenance.5 Thus, while genetic ablation of VEGF-A causes embryonic lethality by preventing initial vessel outgrowth, knockout of angiopoietin-1 allows for initial vascular network formation, but these primitive vessels fail to mature, do not properly incorporate supporting smooth muscle cells, and begin to regress.8 A vessel maintenance or survival role for angiopoietin-1 has been supported by in vitro studies, which show that, although angiopoietin-1 differs from VEGF-A in that it cannot promote endothelial cell proliferation, it can indeed support endothelial survival.9,10 Interestingly, just as VEGF-A and angiopoietin-1 seem to play sequential and complementary roles during blood vessel development, recent studies indicate that VEGF-C/D and angiopoietin-2 similarly play sequential and complementary roles during lymphatic vessel development.11 The more recently described angiopoietin-2 also seems to play important roles during blood vessel remodeling, at least in some settings.11,12 In addition to the insights from genetic ablation studies, administration of angiopoietin-1 has suggested that it can lead to circumferential vessel growth in the absence of new vessel sprouting, and that it has opposing effects on vascular permeability compared with VEGF-A;13–15 ie, while VEGF-A promotes vessel leak, angiopoietin-1 seems to stabilize the vessel wall and prevent vascular leak. So what is the rationale for studying angiopoietin-1 in pulmonary hypertension? It turns out that the rationale differs depending on one’s view of the cellular basis of this disease. One view, adopted by the Thistlethwaite group,1 is that the underlying cellular defect may involve abnormal activation and proliferation of vascular smooth muscle cells surrounding small pulmonary arteries and terminal arterioles, leading to their constriction and inability to dilate, thus resulting in The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association. From Regeneron Pharmaceuticals, Inc, Tarrytown, NY. Correspondence to George D. Yancopoulos, Regeneron Pharmaceuticals, Inc, 777 Old Saw Mill River Rd, Tarrytown, NY 10591. E-mail [email protected] (Circ Res. 2003;92:947-949.) © 2003 American Heart Association, Inc.