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J Appl Physiol 98: 1092-1100, 2005; doi:10.1152/japplphysiol.01017.2004
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HIGHLIGHTED TOPICS
Pulmonary Circulation and Hypoxia

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

Jann Rhodes

Department of Biological Science, College of Veterinary Medicine and Biomedical Science, Colorado State University, Fort Collins, Colorado


   ABSTRACT
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 ABSTRACT
A BRIEF HISTORY OF...
 INTRA- AND INTERSPECIES...
 POTENTIAL DETERMINANTS OF INTRA-...
 SUMMARY AND PERSPECTIVE
 ACKNOWLEDGMENTS
 REFERENCES
 
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, Ca2+ 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.

hypoxia; high altitude

IT IS AXIOMATIC that some humans are prone to develop hypoxic pulmonary hypertension, whereas others are not. Also, among mammalian species living at altitude, some are prone to develop pulmonary hypertension and others do not. The variable nature of the pulmonary circulatory response to chronic hypoxia both within and among species is one of the more puzzling aspects of the lung circulation. Furthermore, because a large signal is easier to study than a small one, interest is often greatest when hypoxic pulmonary hypertension is most severe. Historically, the bovine species provided the first clinical indication of hypoxic pulmonary hypertension and became the first animal model for the study of the disorder. Interestingly, it is the bovine, among mammalian species, that exhibits the most severe chronic hypoxic pulmonary hypertension. For these reasons, it seems appropriate to explore the history of hypoxic pulmonary hypertension in the bovine species and to see how the lessons learned have led to studies in comparative physiology.


   A BRIEF HISTORY OF BRISKET DISEASE
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We know that out of the large number of people who move from a low to a high altitude there is a small percentage who never become acclimated, and who either die of heart failure or move to a lower altitude. Is there any reason why cattle should not be subject to the same rules (66)?

In 1913, George Glover and Issac Newsom began to systematically investigate the pathological changes associated with the agricultural malady known as brisket disease for the sole purpose of advising Colorado and New Mexico stockmen of measures they could take to protect their herds (27). It is interesting to look back, with the benefit of the last 95 years of research, and appreciate the remarkable insight that Glover and Newsom unknowingly possessed about hypoxia-induced heart failure and altitude acclimation. Within 2 years, Glover and Newsom deduced that 1) altitude was the chief causative factor of brisket disease; 2) the disease was more prevalent and severe in lowland cattle transported to higher altitudes; 3) shipping stricken animals to lower altitudes could "effect a cure"; 4) lowland cattle should be gradually introduced to higher altitudes; 5) using "native" highland bulls for breeding would improve the overall hardiness of the herd; and 6) brisket disease was associated with "exhaustion of the heart" (24). In the subsequent year, they catalogued heart weights from over 360 cattle and discovered that hearts from highland cattle (i.e., those grazing between 6,800 and 10,000 ft.) weighed more than those acquired from lowland cattle, thus concluding that brisket disease was due to heart failure for which "the remedy lies not in drugs, but in breeding a hardier strain of cattle" (25).

For over 30 years, the interest in brisket disease waned, and no single person can be given complete credit for deducing the connection between brisket disease and hypoxia-induced pulmonary hypertension. In the early 1940s, Rue Jensen (27), one of Issac Newsom's veterinary students at the School of Veterinary Medicine of Colorado State University, revived an interest in the study of brisket disease. Through his work as a veterinarian, Jensen discovered that heart failure in cattle with brisket disease involved the dilation and failure of the right ventricle (RV), not the entire heart as reported by Glover and Newsom (27). In 1956, Jensen, with fellow veterinarian Robert Pierson (68), reported in a veterinary textbook that "atmospheric hypoxia causes pulmonary changes which leads to increased resistance to circulation through the lungs and failure of the right ventricle" as the etiology of brisket disease. At this time, however, they did not speculate as to the nature of these pulmonary changes.

Initially, Jensen, along with his graduate student Archibald Alexander (1), pursued the idea that emboli or excessive erythrocytosis were among those "pulmonary changes" that led to brisket disease; neither of which appeared to play a role. However, they did discover that the increase in heart weight in cattle with brisket disease was due specifically to RV hypertrophy (1). Shortly thereafter, the fortuitous collaboration in the early 1960s between the pathologists Alexander and Jensen, the cardiologists Grover and Reeves, and the physiologist Will (72a), led to a series of landmark experiments, the first of which included the first study to measure pulmonary arterial pressure in cattle at altitude (10,000 ft.) (6). As a result, they identified the linear relationship between the severity of RV hypertrophy and the magnitude of mean pulmonary arterial pressure (Ppa) and thus established a direct relationship between hypoxia, an increase in pulmonary vascular resistance, and RV hypertrophy (Fig. 1). Also of note was the use of 100% O2 to test whether hypoxic pulmonary hypertension could be relieved by acute hyperoxia. Indeed, oxygen did reduce hypoxic pulmonary hypertension; however, pulmonary pressure remained significantly higher than that measured at low altitude.



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  		Fig. 1. Comparison of mean pulmonary arterial pressure with the ratio of right ventricle to the total ventricular mass (RV/T) between control and high-altitude (HA) yearling Hereford steers. Redrawn from Alexander et al. (6).

 
Building on this work, Alexander and Jensen (2–5) documented, in detail, the pulmonary vascular morphometry of both normal and brisket disease cattle. For the first time, the muscularization of pulmonary arteries and veins as small as 20 µm in the normal bovine lung were identified (2) and arteriographs depicted a process dubbed "vascular pruning" or "dearborization" of the small muscular pulmonary arteries in brisket disease cattle (3). Alexander and Jensen clearly recognized the importance of this last observation as they noted that "because of the present studies of lungs from cattle with high mountain disease, an emphasis was placed upon the small pulmonary arteries in subsequent histological investigations" (3). In that subsequent experiment (5), they made the seminal discovery that the magnitude of mean Ppa developed in response to chronic hypoxia was positively correlated to the degree of medial hypertrophy of the small pulmonary arteries (Fig. 2). This was a crucial observation, as it identified the smooth muscle layer of the small pulmonary arteries as the primary locus of chronic hypoxic pulmonary hypertension.



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  		Fig. 2. Plot of final pulmonary arterial pressure and mean ratio of medial to intimal mass of the small pulmonary arteries and arterioles in control steers and steers that exhibited moderate and severe hypoxic pulmonary hypertension. Redrawn from Alexander and Jensen (5).

 
By 1962, it was clear that cattle subjected to chronic hypoxia displayed a significant and progressive increase in Ppa, the magnitude of which was directly related to the degree of medial hypertrophy of the small pulmonary arteries. Erythrocytosis did not contribute to the increase in mean Ppa, and cardiac output remained essentially normal; thus the profound structural remodeling of the pulmonary vasculature in cattle appeared to be the foundation of hypoxic pulmonary hypertension. In 1963, Grover et al. (28, 29) designed an experiment to determine whether the development of chronic pulmonary hypertension in cattle could be accelerated by exposing the animals to an altitude of 12,700 ft. instead of 10,000 ft. The onset and severity of pulmonary hypertension was greatly accelerated by decreasing atmospheric PO2 a mere 10 Torr. As with the studies at 10,000 ft., the administration of 100% O2 to a subgroup of animals again demonstrated that hypoxia-induced vasoconstriction contributed to the development of pulmonary hypertension, and, with time, hypoxia "increases the capacity of the pulmonary vessels to constrict " (29). More important was the observation that eliminating the vasoconstrictive component of the response did not return mean Ppa to normal (i.e., preexposure) levels and that this "vascular obstruction" also increased progressively with time. For the first time, hypoxic pulmonary hypertension was hypothesized to involve two interrelated processes: a progressive increase in arterial vasoconstriction due, in part, to vascular smooth muscle hypertrophy and relatively fixed "obstruction" of the pulmonary arteries. In retrospect, the results of this study became the foundation for the next 40 years of the research in the field of hypoxic pulmonary hypertension.


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Thus, when a population of normal individuals is subjected to the stimulus of chronic hypoxia, the hyperreactors have the opportunity to distinguish themselves from the hyporeactors, and the entire gamut of pulmonary hypertension appears (30).

Despite all that had been deduced about brisket disease and the development of hypoxic pulmonary hypertension by 1963, it remained puzzling why some cows developed extraordinarily high Ppa at altitude, whereas others exhibited only a moderate increase in pressure. Construction of a histogram of RV to total ventricular weight (RV/T) from both normal and brisket disease cattle clearly illustrated the extraordinary variability in RV hypertrophy among highland cattle (Fig. 3). The distribution of RV hypertrophy found among highland cattle with brisket disease resembled a flat, bell-shaped curve, whereas 98% of RV/T data collected from normal cattle was tightly clustered across two intervals (1). A similar effect was noted for mean Ppa at altitude. At low altitude (i.e., 5,000 ft.), mean Ppa in cattle consistently falls between 25 and 28 mmHg; however, within 2 wk at an elevation of 10,000 ft., mean Ppa becomes quite variable and, after 7 wk, cattle with brisket disease not only develop significantly higher mean Ppa than the rest of the altitude cohort, but as a group, display the greatest variability (6).



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  		Fig. 3. Histogram of the RV/T of hearts of normal cattle and those with brisket disease (BD). Redrawn from Alexander and Jensen (1).

 
The remarkably vigorous response to hypoxia displayed by cattle in general and the significant variability in the magnitude of this response among individual cows provoked the following question: do other species develop hypoxia-induced pulmonary hypertension and do they display the same degree of variability? Early experiments conducted at altitude in the cat, rabbit, and lamb (73, 74) demonstrated that other species do not exhibit the same virulent pulmonary vascular response to chronic hypoxia as cattle. In fact, some species, such as sheep, appear relatively unaffected by chronic hypoxia, although they display an acute pressor response approximating that of cattle (12, 74, 79, 103). Rounds et al. (79) hypothesized that the decrease in cardiac output exhibited by sheep at high altitude acts to attenuate the increase in mean Ppa associated with chronic hypoxia. Several other species, such as the llama, human, goat, coatimundi, and sheep, also display a minimal increase in Ppa after chronic hypoxia that is accompanied by either a slight increase or slight decrease in cardiac output (12, 34, 37, 79, 94, 103). Interestingly, cattle appear to be the exception as cardiac output falls precipitously in Holstein calves at altitude, although they develop a markedly higher mean Ppa than that of Hereford calves that exhibit a slight decrease in cardiac output (100, 103).

Interestingly, there remains a considerable degree of individual variability even in species that develop mild to moderate pulmonary hypertension at altitude (12, 73, 74, 90). Will et al. (101) were able to distinguish individual cattle deemed "susceptible" to hypoxic pulmonary hypertension from those classified as "resistant" based on the magnitude of the acute pressor response. However, this is not the case in other species, the epitome of which is the coatimundi (Nasua narica), a species with a vigorous pressor response to acute hypoxia (35) that exhibits only a minimal increase in mean Ppa in response to chronic hypoxia (34). Thus, with the exception of cattle, the acute pressor response to hypoxia does not necessarily predict the magnitude of pulmonary hypertension elicited by chronic hypoxia (73).

Concurrent with these early studies were those conducted by Best and Heath (15), noting that the amount of medial smooth muscle comprising the small muscular pulmonary arterioles also varies significantly between species; that of Hultgren et al. (46), who were among the first to describe marked intraspecies differences in RV hypertrophy at sea level and altitude; and Harris et al. (36), who documented differences in mean Ppa between animals residing at low altitude (sea level or 10,000 ft.) and their species-specific counterparts indigenous to higher altitudes (>14,000 ft.). Unfortunately, comparisons between studies involving species indigenous to high altitude are somewhat restricted due to the limited number of animals included in each study. In general, most indigenous high-altitude species, such as the llama and yak, exhibit only a moderate degree of pulmonary hypertension, mild RV hypertrophy, and minimal arterial medial thickening in their native habitat compared with species-specific controls at lower altitudes (8, 36, 41, 42). However, mild pulmonary hypertension can still be elicited in llamas raised at sea level in response to chronic hypoxia (12).

Species indigenous to high altitude also exhibit intraspecies variability with regard to mean Ppa, RV hypertrophy, and cardiac output (8, 46), although it is less evident in the llama and yak than in other domestic species such as goats, sheep, guinea pigs, rabbits, dogs, and lambs (7, 46). When Himalayan cattle are cross-bred with the yak and llama (i.e., dzo and stols), a significant degree of variability in pulmonary hemodynamics is introduced, although Himalayan cattle are less "susceptible" to hypoxic pulmonary hypertension than Herefords at a comparable altitude (8). Interestingly, Peruvian Brown Swiss steers also exhibit a minimal degree of RV hypertrophy and less statistical variability compared with Herefords, suggesting that indigenous high-altitude cattle or breeds introduced to high altitude decades earlier, evolve or become less sensitive to the cardiopulmonary effects of chronic hypoxia (46).

Contemporary studies conducted in Leadville, Colorado, (10,150 ft.) on school-age children (ages 13–17) also indicated a substantial degree of individual variability in mean Ppa and RV hypertrophy among young high-altitude residents (97). Most of the children displayed a variable, but definitive, rightward shift in the mean QRS axis, and a subgroup of children exhibited a substantial degree of variability in mean Ppa at rest and during acute hypoxia or exercise. At rest, some students exhibited mean Ppa comparable to that of lower altitudes (i.e., Denver) and displayed only a moderate increase in mean Ppa with acute hypoxia, whereas others, with evidence of pulmonary hypertension at rest, exhibited a dramatic increase in mean Ppa with acute hypoxia. Interestingly, the students with the highest mean Ppa with exercise experienced the greatest fall in Ppa when supplemental oxygen (i.e., 44%) was administered, insinuating a functional (i.e., pulmonary vascular reactivity) rather than structural (i.e., medial hypertrophy) change as the underlying mechanism. Vogel et al. (97) suggested that, as with cattle, the human population is comprised of those who display a minimal response to hypoxia, i.e., hyporeactors, and those who exhibit a vigorous response, i.e., hyperreactors, and that this dichotomy could be used clinically to explain the array of pulmonary vascular responses presented by patients with common pulmonary diseases.

Thus most mammalian species studied to date respond to chronic hypoxia with an increase in mean Ppa. However, species as a whole, as well as individuals within each species, display a marked degree of variability in the magnitude of pulmonary hypertension and degree of RV hypertrophy elicited under comparable conditions. Obviously, nature has selected characteristics that confer an advantage to species that inhabit alpine niches. There is no consensus, however, as to the physiological characteristics that will distinguish those individuals most susceptible to the effects of chronic hypoxia from those less susceptible. The mechanism(s) defining these inherent differences in "reactivity" remain elusive.


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... nor that there is any special type of individual who is more susceptible than another; fat plethoric individuals seem to be as immune as the thin, lean type. Certain people, however, seem to enjoy natural immunity for no apparent cause, whether short and stout, tall and thin or of perfect development (20).

Vascular smooth muscle.   On the heels of these studies, Tucker et al. (92) conducted an experiment to examine the anatomic changes in the small pulmonary arteries of several different species exposed to chronic hypoxia (1–4 wk). As a result, a linear relationship was found between the amount of medial smooth muscle present in the small pulmonary arteries of a species under ambient conditions (i.e., 1,600 m) and the magnitude of pulmonary hypertension and RV hypertrophy developed in that species in response to chronic hypoxia. Although Grover (30) credits Wood (104) and Short (85) with first using the terms "hyperreactive" and "hyporeactive" to describe the pulmonary vascular response to hypoxia, it was the study of Tucker et al. (92) that defined a pulmonary vascular reactivity "hierarchy" based on the amount of medial smooth muscle comprising the small pulmonary arteries and arterioles at low altitude. On the basis of this study, the calf and pig are classified as hyperresponders, the sheep, rabbit, guinea pig, and dog as hyporesponders, and the rat as a moderate responder (Fig. 4). Further support for this hypothesis is found in the anatomic and physiological studies of animals indigenous to high altitude, such as the llama and related species (7, 8, 12, 41, 42), yak (7, 43), Tibetan snow pig (i.e., Himalayan marmot) (88), guinea pig (90, 91), pika (22, 49, 82), Tibetan sheep (48, 81), and viscachas (44), which all have thin-walled pulmonary arteries and only mild to moderate levels of pulmonary hypertension. The coatimundi is again an exception. The pulmonary arteries of coati are similar in thickness to cattle; however, mean Ppa is only marginally increased after 6 wk at a simulated altitude of 16,000 ft. (34, 35).



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  		Fig. 4. Interspecies comparison of right ventricular systolic pressure (RVs) in control animal (0 wk) and altitude-exposed animals at 4,500 m. Hyperresponder (calf and pig), moderate responder (rat), hyporesponder (sheep, rabbit, dog, guinea pig). Redrawn from Tucker et al. (92).

 
The differences in pulmonary vascular structure and the pulmonary response to hypoxia between high-altitude species and their low-altitude species-specific counterparts is now fairly well described; however, why species display such marked differences in pulmonary artery structure and vascular remodeling in response to the same hypoxic stimulus still remains largely unanswered. Are there specific factors in high-altitude species that are responsible for maintaining the thin-walled nature of the small pulmonary arteries? A recent comparative study of Wistar rats exposed to 4,300 m and pika (Ochotona curzoniae) indigenous to 4,300 m identified a high density of tryptase-positive mast cells and transforming growth factor (TGF)-{beta}1-positive neutrophils and mononuclear cells within the connective tissue surrounding the hypertrophied small pulmonary arteries of the Wistar rats (22). Both factors were conspicuously absent in the pika, as was any evidence of pulmonary vascular remodeling. Although the role of mast cell density in chronic hypoxic pulmonary hypertension has been somewhat controversial over the years, perhaps this is an important distinction between some high- and low-altitude species. It is intriguing that TGF-{beta}1-positive neutrophils and mononuclear cells were found in the perivascular sheath of the small pulmonary arteries. Hypoxia (86) and TGF-{beta}1 (38) both stimulate the differentiation of vascular fibroblasts into myofibroblasts, a crucial step in hypoxia-induced vascular remodeling (17). Also, the presence of neutrophils and mononuclear cells within the connective tissue of the pulmonary vessels implicates circulating blood cells as a potential source of growth factors in vascular remodeling process reminiscent of that described for the systemic circulation (40). Recently, Davie et al. (18) reported that the vasa vasorum of the pulmonary vascular bed increases significantly in neonatal calves exposed to hypoxia and may serve as a conduit by which circulating vascular progenitor cells are delivered to the pulmonary arterial adventitia.

A new variant of the transcription factor HIF-1{alpha} was also recently identified in the pika. This new HIF-1{alpha} cDNA sequence, which is modestly expressed in the lung, lacks 133 bp, which shifts the open reading frame and ultimately encodes a protein that lacks the oxygen-dependent degradation domain, both transactivation domains, and the nuclear targeting sequence (105). Additional studies are needed to determine whether this protein is physiologically active and whether this represents an isolated adaptation. If this variant is functional, these changes will have significant implications given the role of HIF in oxygen sensing and the upregulation of genes involved in hypoxia-induced vascular remodeling and cell proliferation.

The complexity of hypoxia-induced medial hypertrophy was underscored by the identification of phenotypically distinct populations of vascular smooth muscle cells in bovine pulmonary arteries (21), introducing the possibility of phenotypically distinct responses to chronic hypoxia within these subpopulations (87). Pulmonary vascular smooth muscle phenotypes have not been characterized in detail in species other than the bovine, and the physiological response of various smooth muscle cell phenotypes to hypoxia have yet to be determined. Finally, the involvement of the Rho/Rho-kinase signaling cascade and the process of Ca2+ sensitization in hypoxic pulmonary hypertension, which is just now being defined (19, 47, 65, 84, 99), may also distinguish hyporesponders from hyperresponders. Thus there are many potential avenues left yet to be explored to determine the specific mechanisms (or the lack thereof) that regulate pulmonary arterial vascular smooth muscle function in high- and low-altitude species.

Collateral ventilation.   Collateral ventilation (CV) has been described in humans (96), dogs (51, 56, 78, 96), cats (96), rabbits (57, 96), sheep (51), and horses (78), but is not found in pigs or cattle (51, 96). CV via the channels of Lambert, Martin, and pores of Kohn are normal airways (58) in that they can participate in maintaining local and regional ventilation-perfusion balance in response to acute hypoxia (50). Reeves et al. (75) found it curious that cattle had relatively thick-walled pulmonary arteries at low altitude where low pulmonary artery pressure prevails. Kuriyama et al. (50) hypothesized that animals that lack CV rely predominantly on hypoxic pulmonary vasoconstriction to adjust ventilation-perfusion mismatches in response to regional hypoxia and, as a consequence, develop pulmonary arterial hypertrophy (i.e., medial hypertrophy) with recurring bouts of hypoxia. In contrast, those species with CV pathways could counter a ventilation-perfusion mismatch incurred by regional hypoxia by moving normoxic air via CV airways into the hypoxic region rather than altering perfusion; and, as a consequence, these species would be characterized by thin-walled pulmonary arteries. In support of this hypothesis, Kuriyama et al. (50) demonstrated that the pig did rely on hypoxic pulmonary vasoconstriction to adjust ventilation-perfusion in response to regional hypoxia, whereas the dog relied on CV.

Interestingly, species with CV also have a lower pressor response to acute hypoxia compared with those species without CV pathways (35). Thus the direct communication between lung segments via CV was proposed as a determinant of interspecies variability in the pulmonary vascular response to chronic hypoxia (51). Using the data reported by Tucker et al. (92) and data generated in their own study, Kuriyama and Wagner (51) found a significant correlation between CV in the dog, sheep, cow, and pig, and pulmonary arterial medial thickness. Although methodological differences make direct comparisons between the studies difficult, if the data are placed in relative order based on the description of the extent of CV, it is in close agreement with reactivity hierarchy described by Tucker et al. (92). CV networks are most extensive in rabbits, cats, dogs, sheep, and horses (i.e., moderate and hyporesponders) but absent in pigs and cattle (i.e., hyperresponders). The coatimundi is again an exception because it lacks CV. As these experiments illustrate, neither the presence nor absence of CV nor the extent of pulmonary arterial medial thickness can predict the degree of pulmonary hypertension that will develop with chronic hypoxia. However, because the coatimundi appears to be a unique exception, we can speculate that high-altitude mammals may have moderate to extensive CV networks; however, these studies have not been conducted. In addition, whether CV is actually beneficial when hypoxia is more "global," as opposed to regional, is also debatable.

Age.   Age has a significant and dramatic impact on hypoxia-induced pulmonary hypertension, right ventricular hypertrophy, and vascular smooth muscle cell hypertrophy and is a critical factor when comparing the physiological response(s) to hypoxia. Glover and Newsom (24) recognized that very young calves were extremely susceptible to the effects of altitude and often died because the ranchers were not cognizant of the symptoms in the young. Pierson and Jenson (68) and Blake (16) actually quantified the incidence of brisket disease by age, and by far the majority of cases (i.e., 75%) occur between birth and 2 years of age. After that, the incidence falls off dramatically (to 3% or less) until the age of 5, at which time incidence climbs again to 20%. However, age alone is not an independent determinant of pulmonary pressure. Will et al. (102) demonstrated that pulmonary arterial pressure increased in all cattle with increasing age at altitude; however, this effect was accelerated in those animals native to sea level compared with native cattle. Experiments conducted primarily in the newborn calf and newborn rat indicate that young animals, initially exposed to hypoxia during the perinatal period, endure more permanent functional and structural changes than adults exposed to a comparable altitude even if allowed to recover in a normoxic environment (72, 93).

Likewise, the normal changes that occur in the pulmonary circulation after birth are either delayed or do not occur in the high-altitude native (64). The extensive electrocardiography and catheterization studies on newborn, infant, adolescent, and adult residents of Morococha, Peru, conducted by Peñaloza et al. (69, 70) have provided the most comprehensive look at the development of the pulmonary circulation in the high-altitude resident. At altitudes above 10,000 ft., the fetal circulatory pattern (i.e., RV dominance, pulmonary hypertension, pulmonary arteriolar hypertrophy) persists after birth but does moderate with age. A modest degree of medial hypertrophy and peripheral muscularization of the small pulmonary arterioles is seen in adult Morococha natives (9–11); and, as a consequence, young Peruvian adults display residual RV hypertrophy and mild pulmonary hypertension (71). Cardiac output and pulmonary arterial wedge pressure in the high-altitude native is not significantly different than that of sea level residents. In addition, the administration of supplemental oxygen has a minimal effect on resting mean Ppa, suggesting that hypoxic pulmonary vasoconstriction contributes nominally to resting mean Ppa and that the structural changes in the vascular tree (i.e., persistent fetal pattern) and/or hypoxia-independent mechanisms of arterial vasoconstriction play a larger role in maintaining pulmonary arterial pressure in the high-altitude native.

Although the gradual regression of peripheral pulmonary artery muscularization after birth is well described (32, 39), very little is known regarding the cellular and molecular mechanism(s) that regulate this process under normoxic conditions, and even less is known about this process at altitude. A recent study by Hall et al. (33) suggests that the mechanisms regulating the regression of peripheral pulmonary arterial muscularization at birth under normoxic conditions are different than those regulating this process after recovery from perinatal hypoxia. Apoptosis and smooth muscle cell replication rates as well as cytoskeletal composition are different depending on vessel type (i.e., conduit or peripheral) and whether regression occurred under continuous normoxic conditions or during recovery from hypoxia. Niermeyer (67) recently reviewed in detail the postnatal cardiopulmonary transition in the high-altitude infant, and, in many respects, this process is delayed; however, why this is the case and how this process is initiated and regulated once it begins is not known. Interestingly, it does appear that there are long-term consequences of transient perinatal hypoxia. In humans, young adults who recover from transient perinatal hypoxic pulmonary hypertension as infants display an exaggerated increase in pulmonary arterial pressure at altitude as adults (36 h, 4,559 m) (83).

On the other end of the spectrum, the incidence of excessive erythrocytosis and chronic mountain sickness (CMS) in high-altitude populations increases gradually with age (52, 60) in association with a gradual decline in ventilation and arterial oxygen saturation (59). Although men exhibit a fairly consistent increase in erythrocytosis and CMS symptoms with time, women display a distinct increase concomitant with menopause (53) and a decrease in progesterone levels (55). Hemoglobin concentration and arterial saturation also varies significantly between high-altitude premenopausal women depending on cycle phase (54) Therefore, age-related changes in sex hormone concentrations, may play a gender-specific role in modulating the cardiopulmonary effects of altitude with age.


   SUMMARY AND PERSPECTIVE
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When one observes the phenomenon of pulmonary hypertension developing in response to the hypoxia of high altitude, it is natural to speculate how this serves the overall bodily economy. We admit that physiological processes need not "serve a useful purpose," but usually they appear to (45).

For years, physiologists have struggled to explain the physiological purpose or advantage of hypoxic pulmonary vasoconstriction. Von Euler and Lilijestrand (98) originally postulated that the purpose of hypoxic pulmonary vasoconstriction was to match or optimize the ratio of alveolar ventilation to regional pulmonary perfusion. This is probably true in instances of regional hypoxia or for many pulmonary disease states; however, when hypoxia is global and sustained, is this still an effective mechanism? In four-legged, deep-chested animals, Grover and Reeves (28) once postulated that hypoxic pulmonary vasoconstriction initially serves to increase pulmonary perfusion pressure and recruit the normally underperfused dorsal region of the lungs, thereby increasing the "effective diffusion capacity." However, as they were well aware, in a relatively short period of time, the benefit to arterial oxygenation is quickly outweighed by the initiation of structural changes throughout the pulmonary vascular bed.

In utero, a relatively high pulmonary vascular resistance must be maintained to ensure that the majority of total cardiac output is diverted away from the lungs and toward the placenta, the primary site of fetal gas exchange. In a relatively early study, Reeves and Leathers (76) demonstrated that newborn calves (i.e., <24 h old) exhibit a virulent pressor response to acute hypoxia, implicating hypoxic pulmonary vasoconstriction as a potential mechanism in sustaining pulmonary vasoconstriction in utero. The substantial amount of vascular smooth muscle in the small pulmonary arteries and arterioles in the fetal lung and the fact that medial thickening of the small pulmonary arteries is one of the hallmark signatures of chronic hypoxia would suggest that both could be derived via a common mechanism. The persistence of fetal pulmonary vascular characteristics in high-altitude infants and children also supports the concept that the mechanism(s) sustaining pulmonary hypertension is a vestige of fetal pulmonary physiology. Therefore, in adults, chronic hypoxic pulmonary hypertension could represent the reactivation of the fetal response to hypoxia.

But why do individuals within a given species respond so differently to hypoxia? In their first publication, Glover and Newsom (24) recognized the importance of genetics in the susceptibility of brisket disease. The idea that the evolutionary history of a population (i.e., length of residence) was a critical factor in determining the pulmonary vascular response to hypoxia was broached by Vogel et al. (97) during the Leadville study. Since that time, a great deal of work indicates that the differences in cardiopulmonary physiology displayed between permanent residents of Tibet, Peru, and, more recently, Ethiopia, do reflect the forces of genetic selection over the course of many generations (13, 14, 31, 61, 80). We assume that the structural and functional characteristics such as a blunted response to acute hypoxia, mild RV hypertrophy, and the moderate degree of pulmonary hypertension displayed by many high-altitude residents of Tibet reflects the successful adaptation to life at high altitude. But what physiological mechanisms have evolved? Are different smooth muscle phenotypes expressed or have specific molecular variants evolved that alter signaling cascades? A variety of vasoactive mediators, growth factors, and, more recently, Rho/Rho-kinases, purportedly plays a role in mediating the pulmonary vascular response to chronic hypoxia (65, 77). Are all involved in distinguishing the hypo- from the hyperresponder? From a clinical perspective, understanding the underlying mechanism(s) that distinguishes hyper- from hyporeactors has significant implications for a variety of cardiac and pulmonary disorders (77).

From an economic perspective, brisket disease is still a significant issue for high mountain ranches in Colorado, Wyoming, Utah, and New Mexico (23). Today, some ranchers catheterize and obtain Ppa measurements on all of their cattle and use it as a selection criteria to define their breeding stock (23, 89). Interestingly, despite all that we know about hypoxic pulmonary hypertension in cattle, the incidence of brisket disease is on the rise, because now, more than ever, cattle are bred primarily for bulk (89). This harkens back to Naeye's (63) survey of hypoxic pulmonary hypertension in extremely obese people. With the escalation in the incidence of obesity in the United States over the last 10 years (26) and the recent spike in pulmonary hypertension in obese people living at moderate altitude (~7,000 ft.) (95), perhaps there is something left to learn from brisket disease. In addition, tens of thousands of tourists travel to a variety of high-altitude destinations around the world on a yearly basis and ~140 million people live above 8,000 ft. (62). Thus 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.


   ACKNOWLEDGMENTS
TOP
 ABSTRACT
 A BRIEF HISTORY OF...
 INTRA- AND INTERSPECIES...
 POTENTIAL DETERMINANTS OF INTRA-...
 SUMMARY AND PERSPECTIVE
 ACKNOWLEDGMENTS
REFERENCES
 
I thank Dr. Jack Reeves for the guidance, encouragement, and invaluable perspective that he so graciously offered in the development of this manuscript and Dr. Robert Grover for advice and input with the finishing touches.


   FOOTNOTES
 

Address for reprint requests and other correspondence: J. Rhodes, Dept. of Biological Science, College of Veterinary Medicine and Biomedical Science, Colorado State Univ., Fort Collins, CO 80523-1683 (E-mail: jann.rhodes{at}colostate.edu)


   REFERENCES
TOP
 ABSTRACT
 A BRIEF HISTORY OF...
 INTRA- AND INTERSPECIES...
 POTENTIAL DETERMINANTS OF INTRA-...
 SUMMARY AND PERSPECTIVE
 ACKNOWLEDGMENTS
 REFERENCES
 

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Endothelin 1, its Endothelin Type A Receptor, Connective Tissue Growth Factor, Platelet-Derived Growth Factor, and Adrenomedullin Expression in Lungs of Pulmonary Hypertensive and Nonhypertensive Chickens
Poult. Sci., May 1, 2007; 86(5): 909 - 916.
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 Circ. Res.Home page
K. R. Stenmark, K. A. Fagan, and M. G. Frid
Hypoxia-Induced Pulmonary Vascular Remodeling: Cellular and Molecular Mechanisms
Circ. Res., September 29, 2006; 99(7): 675 - 691.
[Abstract] [Full Text] [PDF]

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