Hypoxic pulmonary vasoconstriction (HPV) is a unique response of the pulmonary vessels to alveolar hypoxia. In global alveolar hypoxia, however, HPV involves the entire pulmonary circulation resulting in increased pulmonary vascular resistance (PVR). Chronic global alveolar hypoxia is accompanied by structural remodeling of pulmonary vessels, which has long been thought to play a major role in the persistent elevation of PVR in chronic hypoxia-induced pulmonary hypertension (PH). However, more recent studies provided evidence that persistent vasoconstriction is an important contributor to chronic hypoxic PH. Furthermore, recent studies using genetic mouse models clearly demonstrated that different mechanisms regulate pulmonary vascular responses to acute, sustained and chronic hypoxia. In order to identify and precisely delineate the contribution of HPV and vascular remodeling to chronic hypoxia-induced PH we would like to initiate this interactive discussion among those interested in this topic.
For most mammals, including humans, ascent to or residence at high altitude is associated with an increase in pulmonary artery pressure (PAP). The initial rise in PAP on exposure to high altitude hypoxia is due to acute hypoxic pulmonary vasoconstriction (HPV)(1) . It is generally accepted that acute HPV is an adaptive response of the pulmonary circulation to a regional alveolar hypoxia, which diverts blood flow from poorly ventilated to optimally ventilated lung segments thereby optimizing ventilation-perfusion matching and gas exchange, though it might merely represent a vestige of fetal pulmonary physiology (2,3). Nevertheless, acute HPV in local alveolar hypoxia is limited to the affected lung segments and is not accompanied by increase in PAP. In global alveolar hypoxia, which occurs at high altitude, however, HPV involves the entire pulmonary circulation resulting in increased pulmonary vascular resistance (PVR).
In humans, pulmonary vascular response to acute hypoxia has two distinct components: a rapid vasoconstriction occurring within a few seconds with maximal elevation in PAP at 15 min, followed after about 40 min by a secondary, more gradual increase in PAP, reaching a plateau at 2 hr and lasting for at least 8 hr (4,5). Similarly, in isolated buffer-perfused rodent lungs and isolated pulmonary artery rings, hypoxia elicits a biphasic response consisting of a transient vasoconstriction lasting about 10–15 min, followed by a sustained constriction that develops more gradually to reach a plateau after 30–40 min (6,7).
Variation in the pulmonary vascular response to acute hypoxia is well documented, both between and within species (2,8). In humans, extreme responders with an exaggerated HPV might be at risk of presenting acutely on arrival at altitude with high-altitude pulmonary edema (HAPE), a potentially fatal non-cardiogenic pulmonary edema (9). Indeed, numerous studies have shown that HAPE-susceptible subjects have a significantly greater increase in PAP in response to acute hypoxic exposure (9-11) . Remarkably, longer duration of the acute hypoxic exposure (2 hr vs. 15 min) at low altitude is associated with less overlap between HAPE-susceptible and HAPE-resistant subjects (12)..
Chronic global alveolar hypoxia also evokes structural remodeling of pulmonary vessels characterized by increased muscularization of distal arteries with extension of smooth muscle cells into previously non-muscularized arterioles (13) . This vascular remodeling has long been thought to play a major role in the persistent elevation of PVR in chronic hypoxia-induced PH as earlier studies have shown the lack of responsiveness to breathing oxygen at high altitude to reverse the rise in PVR in acclimatized lowlanders and high altitude residents (14-16) . However, more recent studies provided evidence that persistent vasoconstriction is an important contributor to chronic hypoxia-induced PH (17) . It was shown that vasoconstrictor and structural mechanisms contribute equally to chronic hypoxia-induced PH in mice (18). In contrast, persistent vasoconstriction, rather than structural changes in the vasculature, is the main underlying mechanism of increased PVR in chronic hypoxia-induced PH rats (19,20) . An interesting observation on the relative contribution of vasoconstrictor and structural mechanisms to chronic hypoxic PH was made in cattle (21) . After several months spent at high altitude, administration of oxygen to a steer with moderate PH reduced PAP to near normal values, whereas in a steer with severe PH led to only a partial reduction of PAP.
Although it is generally assumed that chronic exposure to hypoxia leads to development of hypoxia-induced PH, not all individuals and not all high altitude ethnic groups are prone to elevated PAP and develop pulmonary vascular remodeling (22-24). For example, Tibetans and Sherpas, who share recent ancestry with the Tibetan highlanders (25), have been reported to have the lowest mean PAP at rest and display no rise in PVR at high altitude (26-28). Moreover, small pulmonary arteries of native Himalayan highlanders are thin-walled with no medial hypertrophy of the pulmonary arteries(29). Interestingly, sea-level Tibetans exhibit blunted pulmonary vascular responses to both acute and sustained hypoxia (30). In the first days of acclimatization to high altitude, Sherpas display lower PAP compared to lowlanders (28). However, no differences between high altitude Sherpas and fully acclimatized sea-level inhabitants have recently been reported (31). It would also be interesting to conduct direct comparisons of PAP between high altitude Tibetans and lowlanders with long-term residence at high altitude.
It has long been anticipated that the mechanisms underlying the pulmonary vascular responses during chronic hypoxia are the same or related to those to acute hypoxia. For example, lowland species with stronger acute HPV develop more severe PH in chronic hypoxia than animals with weaker HPV (3). In cattle, a correlation between strength of acute HPV and severity of chronic hypoxia-induced PH has been observed (32). Interestingly, susceptible calves display pulmonary medial hypertrophy even before their exposure to chronic hypoxia (33). In a study of Kyrgyz high-altitude residents 10-year follow-up revealed progressive increase of PAP in those with an exaggerated HPV and no change in normally responsive highlanders (34). However, no correlation between the magnitude of the acute HPV and the severity of chronic hypoxia-induced PH was observed in other species. For example, though coatis have a vigorous acute HPV (35), they do not develop PH and right ventricular hypertrophy (RVH) in response to chronic hypoxic exposure and do not display muscularization of pulmonary arterioles (36). On the contrary, despite a relatively weak HPV response to acute hypoxia in guinea pigs, they develop chronic hypoxic PH with structural remodeling of pulmonary vessels and RVH (37).
Recent studies using genetic mouse models clearly demonstrated that various signaling pathways regulate pulmonary vascular responses to acute, sustained and chronic hypoxia (38-40). For example, TRPC6-deficient mice display sustained HPV and chronic hypoxia-induced PH with pulmonary vascular remodeling despite disrupted acute HPV (39). In contrast, TRPC1 disruption does not impair the acute HPV while diminish development of pulmonary vascular remodeling in chronic hypoxia (38).
In summary, HPV plays a pivotal role in the pathogenesis of HAPE. New evidence suggests that pulmonary vasoconstriction may play an important role in chronic hypoxia-induced PH. Successful adaptation to life at high altitude might involve genetic adaptation of the different signaling pathways regulating pulmonary vascular responses to acute, sustained and chronic hypoxia.
The question for interactive discussion
Based on the above described scientific and clinical facts, ideas and suggestions, we would like to postulate the following question: what is the relative contribution of acute and sustained HPV and vascular remodeling to chronic hypoxia-induced PH in humans? Our question is directed to all scientists, clinicians and others interested in this topic across the world to try to answer and expose their own views, perspectives and visions in the next volume/issue of the PVRI Chronicle.
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