Longitudinal Heterogeneity in Hypoxic Pulmonary Vasoconstriction

One of the first questions raised by the discovery of HPV by Von Euler and Liljestrand (90), and their immediate recognition of its potential for controlling regional V/Q, was that of the anatomical site of the constriction. This question evokes the concept of longitudinal (arterial to capillary to venous) heterogeneity in the ability of the vessels to respond to hypoxia. Clearly, the V/Q regulating potential of the response would have the finest resolution if the response were restricted to vessels no larger than those serving a functional ventilatory unit. Duke (19) carried out what has become an often-repeated (15) experimental approach to address the HPV site of action. In this experiment, the lungs are perfused using an extra-corporeal perfusion system and ventilating gas mixtures that allow pulmonary arterial Po2 and alveolar (along with pulmonary venous) Po2 to be controlled independently. Likewise, pulmonary venous Po2 and alveolar (along with pulmonary arterial) Po2 can be independently controlled while perfusing the lungs in the retrograde, pulmonary vein to pulmonary arterial, direction. Duke (19) found that decreasing alveolar Po2 was sufficient and, under the conditions of her experiments, necessary to provoke HPV. Decreasing pulmonary arterial or venous Po2 while maintaining high alveolar Po2 produced no response. The conclusion was that HPV occurred in the pulmonary capillaries. Several studies have inferred that pulmonary capillary blood volume decreases in response to acute alveolar hypoxia (14, 15), and there is anatomical evidence that the capillaries are capable of responding to hypoxia (48). However, there is little direct evidence for hypoxia induced constriction of individual capillaries (92), and the concept presently has a low profile.

Subsequently, direct observations have revealed that hypoxia can cause pulmonary arteries and veins to constrict (3, 83), with the response being most intense in the small arteries (3, 25, 83, 84). It also seems clear, from studies on isolated arteries and arterial smooth muscle cells (59, 88), that the smooth muscle cells include both the sensing and contractile machinery. Thus, the search for a humoral mediator that carries the message from 02 sensor cells to contracting cells has been essentially abandoned. The observation that alveolar hypoxia is so much more an effective stimulus than pulmonary arterial hypoxia has been a major reason that the humoral mediator concept has been difficult to give up. The fact that pulmonary arterial (mixed venous) blood is always hypoxic compared to alveolar gas is the reason that HPV has the potential for matching perfusion to ventilation in the first place. Thus, there would be no obvious benefit to having pulmonary arteries responsive to pulmonary arterial However, from an anatomical and gas transport point of view, it is still not entirely clear how it is that the relevant arterial vascular smooth muscle is more affected by alveolar than pulmonary arterial Po2. There is evidence that gas exchange can occur between alveolar air and blood in small arteries (15), as it can between tissue and arteriolar blood in systemic vascular beds (80), i.e., that the vessel wall Po2 can be affected by alveolar Po2. There has not been a clear demonstration that it is sufficient to explain the dominance of alveolar Po2 as the stimulus.

Longitudinal heterogeneity in the pulmonary arterial hypoxic response is demonstrated by observations such as those in Figure 1 wherein the changes in vessel diameters in response to hypoxia can be compared with those in response to the infused vasoconstricting agent serotonin. The comparison reveals that while only the smaller vessel diameters decreased during hypoxia, the larger vessels were fully capable of constricting as much as smaller arteries in response to a different stimulus. Thus, the vessel size dependence in the hypoxia response cannot be attributed simply to a nonspecific size dependent contractility gradient. In the Figure 1B experiment wherein the flow was held constant, the larger vessels in the range studied were actually distended by the pressure increase resulting from the downstream constriction. That is not to say that hypoxia did not activate the smooth muscle in the larger vessels. In fact, with passive distension alone, the large vessels would have been even larger as indicated in Figure 1B. Thus, although more effective in the small vessels, hypoxia can activate arteries as large as 1.5 mm, and probably larger, in the dog lung.

The observation that rather large pulmonary arteries, and smooth muscle cells isolated from their walls, have the capacity to constrict within the normal range of mixed venous Po2 led Marshall et al. (63) to consider the influence of the vasa vasorum, which supplies the larger vessel walls with systemic arterial blood. From observations using extracorporeal manipulation of the Po2 of the bronchial arterial blood supply to the pulmonary arterial vasa vasorum in sheep, they concluded that the effect of the higher Po2 of the vasa vasorum explains the relative insensitivity of pulmonary arteries to their own luminal Po2 in vivo. Data such as those in Figure 1B in isolated lungs and observations on reactivity in different sized isolated pulmonary arteries (5, 59) suggest that the systemic arterial supply to the vessel wall is not the only reason for the vessel size dependence. Heterogeneity in the population of smooth muscle cell phenotypes probably contributes as well, as suggested by the observations of Archer et al. (5) that the vessel size dependence in hypoxia reactivity of isolated pulmonary arterial rings was correlated with the relative distributions of three electro-physiologically distinct smooth muscle cell phenotypes.

Passive Distension

Control

1/Hypuxia r , Serotonin T

400 WO «00 1000 12V0 Control Diameter (pm)

Figure 1. A: X-ray angiographic images of pulmonary arteries in a pump perfused dog lung obtained during the control condition (alveolar Po2 = 106 Torr) and during hypoxia (alveolar Po2 « 36 Torr) or during infusion of serotonin at a rate producing about the same increase in perfusion pressure as during hypoxia. During serotonin infusion, vessels throughout the observable size range are narrower than their respective control diameters. During hypoxia the smallest vessels are narrower than in the control image. Whereas, the largest vessels have been distended. B: The percent changes in arterial diameter produced by hypoxia or serotonin infusion obtained from experiments of the type producing the images in A. Again the smaller vessels narrowed in response to hypoxia. Whereas, when serotonin was infused, the vessels were narrowed throughout the size range studied. The average increase in perfusion pressure in these constant flow experiments was from a control pressure of about 7 to -16 mmHg with both hypoxia and serotonin infusion. The dashed line labeled "Passive Distension" indicates the increase in diameter occurring with the same increase in pressure produced by increasing venous pressure instead of by vasoconstriction. It demonstrates that all vessels in the size range studied were activated by hypoxia even though some did not narrow and were actually distended by the increase in pressure (Modified from Ref. 3)

As indicated in other chapters, pulmonary arterial smooth muscle cells have become the model system for studying the mechanisms of HPV. However, normal pulmonary arteries smaller than about in diameter, which have few if any smooth muscle cells, constrict in response to hypoxia as well as the larger vessels from which smooth muscle cells are normally harvested (37, 92). In fact, it may be that the smaller "non-muscular" but hypoxia sensitive vessels actually have more influence on local blood flow control than the larger vessels from which muscle cells are usually isolated (3).

Passive Distension

Control

1/Hypuxia r , Serotonin T

As indicated above, the location of the flow diverting vessels upstream from the most relevant stimulus has been difficult to reconcile with a complete theory that includes the anatomical, gas transport, and cell signaling factors involved. In addition, the upstream site of action may have been important in guiding the evolution of modulating mechanisms. Several adaptations of the experiment for dissociating alveolar and vascular hypoxia (15, 19) have confirmed that alveolar hypoxia is the most effective stimulus, but they have revealed that pulmonary arterial hypoxia can contribute as well (15, 40). Using a version of that experiment, Hyman et al. (40) isolated the perfusion to a lobar artery of the cat lung so that they could independently control lobar arterial and alveolar Po2 in vivo. When they maintained a constant lobar venous Po2 (an approximation of, or a lower bound on alveolar Po2) of about 92 Torr while perfusing the lobe with a constant flow ofblood with varying lobar arterial Po2, they obtained the results presented in Figure 2, wherein the pulmonary artery pressure began to rise when the lobar arterial Po2 was decreased through the range including what might be considered normal mixed venous Po,.

Figure 2. The lobar arterial pressure response to decreasing lobar arterial Po2 in the left lower lobe of a cat lung perfused with constant flow in situ. The lobar venous P02 (as an approximation of lobar alveolar Po2) was held constant at 92 Torr over the entire range of lobar arterial Po2. (Modified from Ref. 40).

Lobar Arterial P02 (Torr)

Figure 2. The lobar arterial pressure response to decreasing lobar arterial Po2 in the left lower lobe of a cat lung perfused with constant flow in situ. The lobar venous P02 (as an approximation of lobar alveolar Po2) was held constant at 92 Torr over the entire range of lobar arterial Po2. (Modified from Ref. 40).

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