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Blood Flow Control During Exercise: Role for the Venular Endothelium?

Hester, Robert L.; Choi, Jaehwa

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Exercise and Sport Sciences Reviews: October 2002 - Volume 30 - Issue 4 - p 147-151
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Abstract

INTRODUCTION

Blood flow to the peripheral circulation, particularly striated muscle, is regulated to maintain a balance between the metabolic demands of the tissue and the delivery of nutrients. Increases in oxygen consumption, as in exercise, result in a linear increase in blood flow, suggesting that the regulation of blood flow is closely tied to the metabolism of the muscle. Though changes in arterial pressure may increase blood flow, the predominant mechanism for the local increase in blood flow is arteriolar vasodilation resulting in a decreased vascular resistance. This increase in blood flow in response to an increased metabolic rate is considered “functional” hyperemia. Because the vasculature is arranged as a series of branching blood vessels, an increase in the diameter of each vessel is required for a maximal increase in flow. Diameters of the terminal arterioles and therefore capillary perfusion are proposed to be controlled by the release of one or more vasoactive metabolites released from the metabolically active tissue. However, the large arterioles or “feed” vessels contribute the major portion of the overall resistance of a vascular bed as evidenced by the large pressure drop across these vessels (Fig. 1). For example, in strenuous muscle contraction, an increase in diameter at all levels of the microcirculation is essential for a full expression of the hyperemia (Fig. 2) (11). Therefore, although the mechanisms controlling the diameter of the upstream arterioles are extremely important in the overall regulation of blood flow, the exact mechanism(s) responsible for the regulation of arteriolar diameter has yet to be determined.

Figure 1
Figure 1:
Branching order of the microcirculation and distributions of pressure within the arteriolar network. Metabolites released from the tissue will vasodilate the terminal arterioles. The mechanism(s) responsible for the “feed” vessels is undetermined.
Figure 2
Figure 2:
Changes in blood flow with vasodilation of only the terminal arterioles (third order and smaller arterioles) compared with vasodilation of both the feed vessels and terminal arterioles (redrawn from (11)).

REGULATION OF FEED VESSEL DIAMETER

The anatomy of the microcirculation is arranged such that feed vessels may be large distances from the metabolically active tissue. The perfusion of multiple muscle fiber “units” has been shown to be controlled by an arteriole branching from larger feed arterioles (Fig. 1). If there is an increase in the metabolism of a small number of units, and the local vasodilation is not sufficient to increase blood flow, then there has to be a vasodilation of more upstream arterioles. Several mechanisms have been proposed to initiate the vasodilation of the upstream arterioles, including myogenic mechanisms (9), conducted vasodilation (11), and flow-dependent vasodilation (8).

The myogenic response is observed when there is a change in transmural pressure, the pressure across the wall of the vessel. An increase in transmural pressure results in a vasoconstriction, whereas a decrease in transmural pressure will result in a vasodilation. For the myogenic mechanism to be important in functional hyperemia, an increase in metabolic rate and resultant vasodilation of the small terminal arterioles would result in a decrease in pressure in the upstream arterioles, causing a myogenic vasodilation and an increase in blood flow. However, to our knowledge and probably due to technical limitations, there have been no studies measuring arteriolar pressure during functional hyperemia. Therefore the overall role of a myogenic mechanism in the regulation of feed vessel diameter has not been clearly defined.

A vasodilation due to localized increases in the production of vasoactive metabolites can be conducted to larger upstream arterioles. This conducted vasodilation occurs when a local change in membrane potential, and the resultant local vasodilation, is conducted along the arteriole as an electrical signal through gap junctions between endothelial and smooth muscle cells, resulting in an ascending vasodilation. This signal is very rapid in nature, traveling at approximately 2 mm·s−1. However, the vasodilation does appear to be limited in distance traveled along the arteriole, and the overall physiological importance in a functional hyperemic response has not been clearly determined.

Flow-dependent vasodilation operates through an endothelium-dependent mechanism. A localized vasodilation results in an increase in blood flow through the upstream arteriole with the increase in total blood flow at the upstream site due to an increased blood velocity. The resultant increase in wall shear stress (WSS = velocity/diameter) stimulates the release of endothelial-derived relaxing factors (EDRFs), resulting in an arteriolar vasodilation and a return of WSS toward normal values. However, there are two concerns about the involvement of this mechanism in functional hyperemia. With a vasodilation there is return in WSS to normal, thus theoretically resulting in a decrease in the release of EDRFs, and a loss of the vasodilation. Additionally there is no evidence that WSS increases during increases in metabolic rate.

These three mechanisms, myogenic, conducted, and flow-dependent, are clearly present in the microcirculation. However, the role that each of these mechanisms play in maintaining a regulation between oxygen consumption and delivery to the tissue during exercise has not been determined.

VENULAR-ARTERIOLAR DIFFUSION OF METABOLITES

One mechanism by which the upstream vessels could sense the metabolic state of the tissue is through a venular-to-arteriolar diffusion of vasoactive metabolites. Anatomically, in most tissues, arteries and veins, along with the smaller arterioles and venules, are paired and this paired arrangement persists throughout many branch orders. However, the physiological consequence, if any, of such an arrangement has been unclear. Arterioles that provide the most resistance to blood flow within a vascular bed are tightly paired with venules, an anatomical arrangement ideal for venular control of the resistance arterioles through the venular-to-arteriolar diffusion of vasoactive metabolites.

Venular blood has for many years been used as an index of conditions at the capillary level. With increases in metabolic rate there are dramatic changes in the composition of venous blood. Depending on the intensity of the increased metabolic rate there are decreases in oxygen levels, with increases in carbon dioxide, hydrogen, potassium, lactic acid, and possibly many other metabolites. Diffusion of vasoactive substances from the venule to arteriole can alter arteriolar diameter and thus increase or decrease blood flow to tissue. This hypothesis was verified by studies in which vasoactive substances were injected into either precapillary vessels or venules. Injection of norepinephrine into precapillary vessels results in an arteriolar constriction upstream from the injection site, at a point where the venule draining the precapillary vessel is parallel to the upstream arteriole (12). Increases in the tissue levels of adenosine result in an upstream arteriolar dilation through the venular-arteriolar diffusion of adenosine (7). With an increase in metabolic rate there will be an increase in metabolite concentrations in the venous blood. Depending on the diffusion rate of the metabolites and the sensitivity of the arteriolar smooth muscle to the specific vasoactive metabolites, there will be an increase in arteriolar diameter, blood flow, and a resultant washout of the vasoactive metabolites.

Of greater interest is the role that venular EDRFs play in the regulation of arteriolar diameter. In the hamster cremaster muscle there is an obligatory role for the venular endothelium in the dilation of its paired arteriole in response to muscle stimulation (10). This is based on the observation that disruption of the venular endothelium after infusion of air into the venule inhibits the paired arteriolar vasodilation in response to an increased metabolic rate. Arterioles adjacent to venules with intact endothelium (venules in which air did not enter) exhibited a normal hyperemic response. Thus, even though there was no experimental manipulation of the arterioles, we were able to significantly attenuate the arteriolar dilation associated with the muscle stimulation by disrupting the venular endothelium. These results suggest that a substance(s) from the venular endothelium is important for dilation of upstream arterioles during muscle stimulation. It is noteworthy that disruption of the venular endothelium is not associated with a change in the resting diameter of the arteriole, suggesting that factors from the venular endothelium are not important for maintaining arteriolar tone under resting conditions in this preparation.

Because a venular EDRF appears to be important in the regulation of arteriolar diameter, the identity of the mediator during functional hyperemia is important. Falcone and Bohlen originally presented work showing the existence of a venular EDRF, presumably nitric oxide (NO) (4). It does not appear that the venular mediator of functional hyperemia is nitric oxide, as a previous study has not supported a role for NO in the functional hyperemic response (1). Metabolites of arachidonic acid, prostanoids, or cytochrome P450 metabolites, are another group of endothelium-derived vasoactive factors that may participate in venular-arteriolar communication. Metabolism of arachidonic acid generates three main groups of eicosanoids: prostanoids (prostaglandins and thromboxane) by cyclooxygenase, leukotrienes by lipoxygenase, and epoxyeicosatrienoic acids (EETs) and hydroxyeicosatetraenoic acids (HETEs) by various cytochrome P450 enzymes (Fig. 3). Though it appears that the venular endothelium can release one or more cyclooxygenase products, prostaglandin I2 (PGI2), also called prostacyclin, appears to be the major metabolite. In response to muscle stimulation, arterioles that are paired with a venule do not vasodilate when treated with the cyclooxygenase inhibitor indomethacin. In contrast, indomethacin treatment had no effect on unpaired arterioles (6). These results support the hypothesis that during increased muscle metabolism, a prostanoid, such as prostacyclin, is released from the venular endothelium and diffuses to and dilates the adjacent arteriole.

Figure 3
Figure 3:
Metabolism of arachidonic acid. Phospholipase A2 (PLA2) initiates the metabolism of arachidonic acid. Activation of cyclooxygenase results in an increase in prostacyclin (PGI2). Activation of various cytochrome P450 enzymes will result in the generation of epoxyeicosatrienoic acids (EETs) and/or hydroxyeicosatetraenoic acids (HETEs).

The release of arachidonic acid metabolites from the venular endothelium, and subsequent diffusion to the arterioles is a potential mechanism for the control of arteriolar diameter. However, to be physiologically relevant, there must be a mechanism by which the venular endothelium can “sense” the tissue metabolic needs. That is, there must be a stimulus originating in the venules, which initiates the sequence of events leading to arteriolar dilation. In contrast to the current data in both humans and animals showing that the arteriolar endothelial cells are not exposed to changes in PCo2, Po2, or pH during increases in muscle metabolism there are dramatic decreases in venous/venular oxygen levels, along with increases in venous/venular carbon dioxide and hydrogen ion levels. Thus, we hypothesize that the venular endothelium senses a change in venous blood chemistry.

Decreases in venous Po2 and increases in venous Pco2 or H+ may initiate the release of EDRFs from venular endothelium. However a direct role for these factors has not been demonstrated and evidence from several studies suggests that an additional signaling pathway is involved. Red blood cells (RBCs) release adenosine triphosphate (ATP) when exposed to hypoxia and hypercapnia. Such release should occur predominantly in the venules where Po2 levels decline as a result of muscle stimulation. When isolated arterioles are perfused with a normoxic physiological salt solution in a low-oxygen tissue bath there is no change in arteriolar diameter (3). However, when RBCs are added to the perfusate there is a release of ATP from the RBCs and a subsequent vasodilation, suggesting that RBCs release ATP when exposed to a low oxygen environment. Thus the release of EDRFs from the venular endothelium is dependent on stimulation by ATP release from RBCs.

Exposure of venous endothelial cells to ATP, both in isolated perfused veins and in culture, results in a significant production of PGI2 (2). At the microcirculatory level increases in venular ATP levels will result in an endothelium-dependent dilation of adjacent arterioles through a mechanism involving cyclooxygenase metabolites (5). ATP infusion into hamster cremaster venules dilates the adjacent arteriole, with the vasodilation blocked by either disruption of the venular endothelium with air bubbles or treatment with indomethacin. Even though increases in venular ATP concentrations will result in the release of prostanoids from the venular endothelium, whether there is an actual increase in venular ATP levels during increases in metabolic rate remains to be elucidated. Nonetheless, these studies suggest that the red blood cell may be essential for communication between venules and arterioles during periods of increased muscle metabolism.

SUMMARY

The hypothesis that the venular endothelium is important in the control of blood flow is based on studies performed in either thin microcirculatory preparations or isolated blood vessels. A major question that still needs to be addressed is whether this mechanism is important in more postural muscles under differing metabolic rates. Also, additional studies would need to determine the importance of this mechanism at different time points throughout an exercise period. Current technical problems preclude clearly testing this hypothesis in larger animals. However, the clear anatomical design of most tissues, in terms of arteriolar-venular pairing, presents an intriguing hypothesis that needs to be tested.

In summary, the increase in blood flow that occurs during exercise requires an integrative response from all levels of the microcirculation, from the terminal arterioles that distribute flow to the feed vessels that regulate flow. The diameter of the terminal arterioles is proposed to be determined by the local concentration of metabolites. In addition to conducted, myogenic, or flow-dependent mechanisms responsible for the control of feed arteriolar diameter, the venular endothelial release of arachidonic acid metabolites provides an additional mechanism to regulate blood flow (Fig. 4). The release of ATP from RBCs in response to hypoxia, hypercapnia, or acidosis, conditions that occur during exercise, could provide a mechanism by which the diameter of feed arterioles can be coupled to the metabolic state of the tissue. These observations suggest that the venular endothelium plays an important role in the local control of blood flow by “sensing” increases in the metabolic needs of the muscle and responding by releasing vasodilatory factors that diffuse to and dilate the adjacent arteriole and increase blood flow.

Figure 4
Figure 4:
Proposed regulation of blood flow during exercise. The vasodilation of the terminal arterioles is dependent on the direct generation of metabolites from the metabolically active tissue. The change in the venous blood, hypoxia, hypercapnia, and/or acidosis would stimulate red blood cells (RBCs) to release adenosine triphosphate (ATP). ATP induced prostanoid release from the venular endothelium would vasodilate adjacent arterioles resulting in an increase in blood flow.

Acknowledgments

This work was supported by grants from the National Institutes of Health (HL-51971, HL-63958) and the American Heart Association Southeast Affiliate Postdoctoral Fellowship.

References

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Keywords:

exercise hyperemia; functional hyperemia; arachidonic acid; ATP

©2002 The American College of Sports Medicine