Hypoxic pulmonary hypertension: hypoxic pulmonary vasoconstriction vs. vascular remodeling

PVRI Member Authors: Argen Mamazhakypov, Abdirashit Maripov, Aleksandar Petrovic, Oleg Pak, Michael Seimetz, Djuro Kosanovic, Akylbek Sydykov


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.


Main Article

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.




  1. Jaenke RS, Alexander AF. Fine structural alterations of bovine peripheral pulmonary arteries in hypoxia-induced hypertension. Am J Pathol. 1973;73:377-398.
  2. Rhodes J. Comparative physiology of hypoxic pulmonary hypertension: historical clues from brisket disease. J Appl Physiol. 2005;98:1092-1100.
  3. Sylvester JT, Shimoda LA, Aaronson PI, Ward JP. Hypoxic pulmonary vasoconstriction. Physiol Rev. 2012;92:367-520.
  4. Talbot NP, Balanos GM, Dorrington KL, Robbins PA. Two temporal components within the human pulmonary vascular response to approximately 2 h of isocapnic hypoxia. J Appl Physiol. 2005;98:1125-1139.
  5. Dorrington KL, Clar C, Young JD, Jonas M, Tansley JG, Robbins PA. Time course of the human pulmonary vascular response to 8 hours of isocapnic hypoxia. Am J Physiol. 1997;273:H1126-1134.
  6. Weissmann N, Akkayagil E, Quanz K, Schermuly RT, Ghofrani HA, Fink L, Hanze J, Rose F, Seeger W, Grimminger F. Basic features of hypoxic pulmonary vasoconstriction in mice. Respir Physiol Neurobiol. 2004;139:191-202.
  7. Wilkins MR, Ghofrani HA, Weissmann N, Aldashev A, Zhao L. Pathophysiology and treatment of high-altitude pulmonary vascular disease. Circulation. 2015;131:582-590.
  8. Grover RF, Vogel JH, Averill KH, Blount SG, Jr. Pulmonary hypertension. individual and species variability relative to vascular reactivity. Am Heart J. 1963;66:1-3.
  9. Hultgren HN, Grover RF, Hartley LH. Abnormal circulatory responses to high altitude in subjects with a previous history of high-altitude pulmonary edema. Circulation. 1971;44:759-770.
  10. Yagi H, Yamada H, Kobayashi T, Sekiguchi M. Doppler assessment of pulmonary hypertension induced by hypoxic breathing in subjects susceptible to high altitude pulmonary edema. Am Rev Respir Dis. 1990;142:796-801.
  11. Vachiery JL, McDonagh T, Moraine JJ, Berre J, Naeije R, Dargie H, Peacock AJ. Doppler assessment of hypoxic pulmonary vasoconstriction and susceptibility to high altitude pulmonary oedema. Thorax. 1995;50:22-27.
  12. Dehnert C, Grunig E, Mereles D, von Lennep N, Bartsch P. Identification of individuals susceptible to high-altitude pulmonary oedema at low altitude. Eur Respir J. 2005;25:545-551.
  13. Arias-Stella J, Saldana M. The muscular pulmonary arteries in people native to high altitude. Med Thorac. 1962;19:484-493.
  14. Groves BM, Reeves JT, Sutton JR, Wagner PD, Cymerman A, Malconian MK, Rock PB, Young PM, Houston CS. Operation Everest II: elevated high-altitude pulmonary resistance unresponsive to oxygen. J Appl Physiol. 1987;63:521-530.
  15. Canepa A, Chavez R, Hurtado A, Rotta A, Velasquez T. Pulmonary circulation at sea level and at high altitudes. J Appl Physiol. 1956;9:328-336.
  16. Hultgren HN, Kelly J, Miller H. Effect of oxygen upon pulmonary circulation in acclimatized man at high altitude. Journal of Applied Physiology. 1965;20:239-243.
  17. Rowan SC, McLoughlin P. Hypoxic pulmonary hypertension: the paradigm is changing. Exp Physiol. 2014;99:837-838.
  18. Cahill E, Rowan SC, Sands M, Banahan M, Ryan D, Howell K, McLoughlin P. The pathophysiological basis of chronic hypoxic pulmonary hypertension in the mouse: vasoconstrictor and structural mechanisms contribute equally. Exp Physiol. 2012;97:796-806.
  19. van Suylen RJ, Smits JF, Daemen MJ. Pulmonary artery remodeling differs in hypoxia- and monocrotaline-induced pulmonary hypertension. Am J Respir Crit Care Med. 1998;157:1423-1428.
  20. Hyvelin JM, Howell K, Nichol A, Costello CM, Preston RJ, McLoughlin P. Inhibition of Rho-kinase attenuates hypoxia-induced angiogenesis in the pulmonary circulation. Circ Res. 2005;97:185-191.
  21. Will DH, Alexander AF, Reeves JT, Grover RF. High altitude-induced pulmonary hypertension in normal cattle. Circ Res. 1962;10:172-177.
  22. Vogel JH, Weaver WF, Rose RL, Blount SG, Jr., Grover RF. Pulmonary hypertension on exertion in normal man living at 10,150 feet (Leadville, Colorado). Med Thorac. 1962;19:461-477.
  23. Peñaloza D, Sime F, Banchero N, Gamboa R, Cruz J, Marticorena E. Pulmonary hypertension in healthy men born and living at high altitudes. The American journal of cardiology. 1963;11:150-157.
  24. Heath D, Smith P, Rios Dalenz J, Williams D, Harris P. Small pulmonary arteries in some natives of La Paz, Bolivia. Thorax. 1981;36:599-604.
  25. Bhandari S, Zhang X, Cui C, Bianba, Liao S, Peng Y, Zhang H, Xiang K, Shi H, Ouzhuluobu, Baimakongzhuo, Gonggalanzi, Liu S, Gengdeng, Wu T, Qi X, Su B. Genetic evidence of a recent Tibetan ancestry to Sherpas in the Himalayan region. Sci Rep. 2015;5:16249.
  26. Groves BM, Droma T, Sutton JR, McCullough RG, McCullough RE, Zhuang J, Rapmund G, Sun S, Janes C, Moore LG. Minimal hypoxic pulmonary hypertension in normal Tibetans at 3,658 m. J Appl Physiol. 1993;74:312-318.
  27. Hoit BD, Dalton ND, Erzurum SC, Laskowski D, Strohl KP, Beall CM. Nitric oxide and cardiopulmonary hemodynamics in Tibetan highlanders. J Appl Physiol. 2005;99:1796-1801.
  28. Faoro V, Huez S, Vanderpool R, Groepenhoff H, de Bisschop C, Martinot JB, Lamotte M, Pavelescu A, Guenard H, Naeije R. Pulmonary circulation and gas exchange at exercise in Sherpas at high altitude. J Appl Physiol (1985). 2014;116:919-926.
  29. Gupta ML, Rao KS, Anand IS, Banerjee AK, Boparai MS. Lack of smooth muscle in the small pulmonary arteries of the native Ladakhi. Is the Himalayan highlander adapted? Am Rev Respir Dis. 1992;145:1201-1204.
  30. Petousi N, Croft QP, Cavalleri GL, Cheng HY, Formenti F, Ishida K, Lunn D, McCormack M, Shianna KV, Talbot NP, Ratcliffe PJ, Robbins PA. Tibetans living at sea level have a hyporesponsive hypoxia-inducible factor system and blunted physiological responses to hypoxia. J Appl Physiol (1985). 2014;116:893-904.
  31. Foster GE, Ainslie PN, Stembridge M, Day TA, Bakker A, Lucas SJ, Lewis NC, MacLeod DB, Lovering AT. Resting pulmonary haemodynamics and shunting: a comparison of sea-level inhabitants to high altitude Sherpas. J Physiol. 2014;592:1397-1409.
  32. Will DH, Hicks JL, Card CS, Reeves JT, Alexander AF. Correlation of acute with chronic hypoxic pulmonary hypertension in cattle. J Appl Physiol. 1975;38:495-498.
  33. Weir EK, Will DH, Alexander AF, McMurtry IF, Looga R, Reeves JT, Grover RF. Vascular hypertrophy in cattle susceptible to hypoxic pulmonary hypertension. J Appl Physiol Respir Environ Exerc Physiol. 1979;46:517-521.
  34. Aldashev AA, Sarybaev AS, Sydykov AS, Kalmyrzaev BB, Kim EV, Mamanova LB, Maripov R, Kojonazarov BK, Mirrakhimov MM, Wilkins MR, Morrell NW. Characterization of high-altitude pulmonary hypertension in the Kyrgyz: association with angiotensin-converting enzyme genotype. Am J Respir Crit Care Med. 2002;166:1396-1402.
  35. Hanson WL, Boggs DF, Kay JM, Hofmeister SE, Wagner WW, Jr. Collateral ventilation and pulmonary arterial smooth muscle in the coati. J Appl Physiol. 1993;74:2219-2224.
  36. Hanson WL, Boggs DF, Kay JM, Hofmeister SE, Okada O, Wagner WW, Jr. Pulmonary vascular response of the coati to chronic hypoxia. J Appl Physiol (1985). 2000;88:981-986.
  37. Thompson BT, Hassoun PM, Kradin RL, Hales CA. Acute and chronic hypoxic pulmonary hypertension in guinea pigs. J Appl Physiol. 1989;66:920-928.
  38. Malczyk M, Veith C, Fuchs B, Hofmann K, Storch U, Schermuly RT, Witzenrath M, Ahlbrecht K, Fecher-Trost C, Flockerzi V, Ghofrani HA, Grimminger F, Seeger W, Gudermann T, Dietrich A, Weissmann N. Classical transient receptor potential channel 1 in hypoxia-induced pulmonary hypertension. Am J Respir Crit Care Med. 2013;188:1451-1459.
  39. Weissmann N, Dietrich A, Fuchs B, Kalwa H, Ay M, Dumitrascu R, Olschewski A, Storch U, Mederos y Schnitzler M, Ghofrani HA, Schermuly RT, Pinkenburg O, Seeger W, Grimminger F, Gudermann T. Classical transient receptor potential channel 6 (TRPC6) is essential for hypoxic pulmonary vasoconstriction and alveolar gas exchange. Proc Natl Acad Sci U S A. 2006;103:19093-19098.
  40. Xia Y, Yang XR, Fu Z, Paudel O, Abramowitz J, Birnbaumer L, Sham JS. Classical transient receptor potential 1 and 6 contribute to hypoxic pulmonary hypertension through differential regulation of pulmonary vascular functions. Hypertension. 2014;63:173-180.

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PVRI Chronicle Vol 3: Issue 1 cover image

March 2016

PVRI Chronicle Vol 3: Issue 1

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