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Effect of Excessive Erythrocytosis on Pulmonary Vascular Smooth Muscle Mass

University of South Alabama Mobile, Alabama

In this issue of the Journal (pp. 829–835), Hasegawa and coworkers (1) present research which shows that pulmonary vascular remodeling in chronic hypoxia may be the result of "either oxygen deprivation or erythrocytosis." Transgenic mice that overexpress the human erythrocytosis gene in an oxygen-independent manner were studied. These mice developed polycythemia, but they had normal blood pressure, heart rate, and cardiac output. Interestingly, pulmonary arterial pressure was greatly increased in vivo, but was actually reduced in blood-free perfused lungs.

First, we need to recall the effects of increased blood viscosity () on cardiac output (Q), where r is blood vessel radius, (P₁ - P_o) is the pressure gradient acting across an organ that produces blood flow, and l is the blood vessel length (2):

In normal blood vessels, when the hematocrit increases from 30 to 70%, blood viscosity increases 4 to 5 times normal, but in vivo viscosity changes only 2 to 3 times in an isolated hindlimb preparation (3, 4)!

The following questions must be raised by these data in the paper of Hasegawa and colleagues: One, how can mice have normal blood pressures, heart rates, and cardiac outputs when hematocrits are also abnormally high? Two, do these mice release pulmonary dilators? Three, is the smooth muscle's ability to contract in the pulmonary circulation abnormal? The results of this study answer these questions because the polycythemia in this experimental model causes an increase in prostacyclin that is also coupled to the expression of endothelial nitric oxide synthase and a decrease in the thickness of pulmonary vascular smooth muscle! These findings explain why these transgenic mice, which express excessive erythrocytosis, have marked pulmonary hypertension in vivo, but not in vitro, i.e., the pulmonary hypertension is obviously due to increased blood viscosity. But the lungs adapt over time by elevating the synthesis of vasodilators, prostacyclin, and nitric oxide, and actually reduce smooth muscle thickness, which reduces pulmonary vascular tone coupled to a lowered vascular responsiveness to vasoconstrictors, such as shown with a thromboxane receptor agonist, U46619.

These changes in lung morphology, especially the decrease in muscle mass in the pulmonary circulation, are very important. They allow blood with a high hematocrit to flow through the lungs during chronic hypoxia by releasing vascular vasodilators and decreasing vascular smooth muscle mass, which results in normal blood pressure, heart rate, and cardiac output, even when the blood contains a very high hematocrit.

This is a remarkable finding that must be further investigated, since it suggests that when an organ such as the lung is subjected to increased blood viscosity, the organ can decrease its vascular smooth muscle mass and maintain a "blood flow" to properly oxygenate the blood. I'm not sure how all of these events occur, but an understanding of this phenomenon will help clinicians to develop proper treatments in patients whose blood viscosity is greatly increased. It would be interesting to know whether or not people who live at higher altitudes can also alter vascular smooth muscle mass in their lungs when hematocrits increase; that is, the higher hematocrit can certainly carry more oxygen to tissues and the lungs respond by somehow decreasing their smooth muscle mass and releasing vasodilators. So far as I can tell, the response mechanism for producing this phenomenon has not been identified as a potential safety factor for the lung's functioning capabilities when humans are exposed to low oxygen environments. A similar mechanism, however, may allow people living in low oxygen environments to better cope and remain free of pulmonary edema, although their bodies produce greater quantities of blood, hemoglobin, pulmonary capillary blood volume, and alveolar surface areas, which, when taken together, allow a more efficient usage of oxygen when living at high altitudes (4). There is absolutely no doubt that when humans, who have not been acclimatized to low PO₂ environments, rapidly develop life-threatening pulmonary edema as they ascend to high altitudes. Perhaps it would be beneficial for mountain climbers or workers exposed to high altitudes to train at low PO₂ levels, which will release vasodilators and decrease pulmonary vascular smooth muscle mass, and by so doing will allow them to work and function at high altitudes.

FOOTNOTES

Conflict of Interest Statement: A.E.T. has no declared conflict of interest.

REFERENCES

1. Hasegawa J, Wagner KF, Karp D, Li D, Shibata J, Heringlake M, Bahlmann L, Depping R, Fandrey J, Schmucker P, et al. Altered pulmonary vascular reactivity in mice with excessive erythrocytosis. Am J Respir Crit Care Med 2004;169:829–835.[Abstract/Free Full Text]
2. Guyton AC. Textbook of medical physiology, 8th ed. Philadelphia: W.B. Saunders Co; 1991. p. 156 and p. 464–467.
3. Berne R, Levy M, editors. Physiology, 4th ed. St. Louis, MO, Washington, D.C., and Toronto, ON, Canada: C.V. Mosby Co.; 1988. p. 582–583.
4. West J, Lahiri S, editors. High altitude in man. Bethesda: American Physiological Society; 1984.

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