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POINT-COUNTERPOINT

Rebuttal from Drs. Thijssen and Hopman

In a series of experiments, Dr. Green and colleagues demonstrated that typical changes in shear pattern, characterized by an increase in retrograde flow, are linked with endothelial NO release in the nonactive regions (4). Although it might be tempting to relate vascular adaptation in inactive regions to alterations in shear pattern, we believe that the truth is not that simple. In nonactive vascular beds during exercise, an enhanced release of vasoconstrictors is present, such as endothelin-1 (5), angiotensin II (7), and vasopressin (8). The actions of these local vasoconstrictors, combined with enhanced activity of the sympathetic nervous system (2), likely outweigh the beneficial effects of NO.

The role for shear rate in exercise-induced vascular adaptations is well recognized, but shear rate is not the only factor involved; unfortunately the truth is never simple. Hypoxia, through release of growth factors such as VEGF, importantly contributes to exercise-induced vascular adaptations (6). Notably, hypoxia and VEGF also contribute to the release and homing of circulating bone marrow-derived endothelial progenitor cells (1). These progenitor cells predict the occurrence of cardiovascular events and death (9), possibly through their capability for endothelial repair, arteriogenesis, and angiogenesis. Appreciating a key role for hypoxia in exercise-induced vascular adaptations casts doubt on vascular adaptations in nonactive muscles during exercise where this essential physiological stimulus is absent (3).

Interestingly, blood flow and related shear patterns vary markedly among different locations and sizes of arteries at rest and during exercise. The prominent retrograde component in the nonactive brachial artery blood flow pattern is hypothesized to result from an increased downstream vasoconstriction (4). In contrast, arteries supplying highly metabolic tissues (i.e., heart and legs) have marked vasodilation and will therefore not demonstrate this blood flow pattern. Therefore, one may question whether findings in the brachial artery during leg exercise can be extrapolated to the coronary vascular bed, since shear rate as well as other physiological stimuli will be markedly different.

Taken together, the central question in this discussion is which stimuli are obligatory, either alone or in combination with others, to result in exercise-induced vascular adaptations in the active and nonactive regions. We enjoyed discussing this topic and hope we presented our arguments in line with Oscar Wilde's "One should always play fairly when one has the winning cards."

REFERENCES

1. Asahara T, Murohara T, Sullivan A, Silver M, van der Zee R, Li T, Witzenbichler B, Schatteman G, Isner JM. Isolation of putative progenitor endothelial cells for angiogenesis. Science 275: 964–967, 1997.[Abstract/Free Full Text]
2. Buckwalter JB, Clifford PS. The paradox of sympathetic vasoconstriction in exercising skeletal muscle. Exerc Sport Sci Rev 29: 159–163, 2001.[CrossRef][Medline]
3. Calbet JA, Gonzalez-Alonso J, Helge JW, Sondergaard H, Munch-Andersen T, Boushel R, Saltin B. Cardiac output and leg and arm blood flow during incremental exercise to exhaustion on the cycle ergometer. J Appl Physiol 103: 969–978, 2007.[Abstract/Free Full Text]
4. Green DJ, Bilsborough W, Naylor LH, Reed C, Wright J, O'Driscoll G, Walsh JH. Comparison of forearm blood flow responses to incremental handgrip and cycle ergometer exercise: relative contribution of nitric oxide. J Physiol 562: 617–628, 2005.[Abstract/Free Full Text]
5. Maeda S, Miyauchi T, Sakane M, Saito M, Maki S, Goto K, Matsuda M. Does endothelin-1 participate in the exercise-induced changes of blood flow distribution of muscles in humans? J Appl Physiol 82: 1107–1111, 1997.[Abstract/Free Full Text]
6. Prior BM, Yang HT, Terjung RL. What makes vessels grow with exercise training? J Appl Physiol 97: 1119–1128, 2004.[Abstract/Free Full Text]
7. Stebbins CL, Symons JD. Role of angiotensin II in hemodynamic responses to dynamic exercise in miniswine. J Appl Physiol 78: 185–190, 1995.[Abstract/Free Full Text]
8. Stebbins CL, Symons JD. Vasopressin contributes to the cardiovascular response to dynamic exercise. Am J Physiol Heart Circ Physiol 264: H1701–H1707, 1993.[Abstract/Free Full Text]
9. Werner N, Kosiol S, Schiegl T, Ahlers P, Walenta K, Link A, Bohm M, Nickenig G. Circulating endothelial progenitor cells and cardiovascular outcomes. New Engl J Med 353: 999–1007, 2005.[Abstract/Free Full Text]

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