Invited Symposium: Hypertension III: Flow-Induced Vascular Remodeling



Materials & Methods


Discussion & Conclusion



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Microvascular Adaptations to Reduced Blood Flow: Introduction of a New Model

Contact Person: Donna H. Wang (dwang@utmb.edu)

Discussion and Conclusion

The relative roles of blood flow and pressure in the regulation of vascular growth is an intriguing problem that has been difficult to solve. The orchidectomy model was designed to reduce the work demand of the cremaster and secondarily cause a reduction in blood flow through the cremaster microcirculation without changing blood pressure or disturbing the perfusion capability of the vessels. The decreased muscle tension from lack of a testicle to support following orchidectomy resulted in a decrease in demand for oxygen and nutrients and probably an initial decrease in blood flow per gram of tissue. Three weeks later, the muscle was smaller than the control muscle because of a decreased rate of growth (Fig. 1) and total blood flow to the muscle was reduced (Tab. 2 and Fig. 2). However, unit blood flow had returned to control levels (Tab. 2 and Fig. 2). Unit flow on both sides (Table 2) was very close to the value of 9.02+2.05 ml/min/100g obtained by Morff and Granger (11) using microspheres. Neither the external spermatic artery (1A) nor the cremasteric artery were disturbed and thus the blood pressure in these vessels should have been entirely normal. Furthermore, both cremaster muscles were exposed to the same circulating levels of testosterone and temperature after unilateral orchidectomy, indicating that the cremaster muscle on the orchidectomy side was exposed to the same conditions as the control side, except for a decreased work load. Thus, this animal model would seem to be useful for studies of changes in skeletal muscle microvasculature caused by decreased blood flow, secondary to reduced metabolic demand.

By comparing the control cremasters in the younger and older rats, the development of the individual arterioles and the arteriolar network can be seen during this period of rapid growth associated with juvenile maturation. As seen in Figure 3, the relaxed diameters of all four orders of arterioles increased with age and the wall area increased proportionately (Fig. 5 and 6). Although the arcading network formed by the 1A and 2A's increased in length and size as the muscle grew (Fig. 4), it did not increase in proportion to the 3 fold increase in muscle mass. The length density, therefore, decreased (Fig. 7). As the arcade enlarged, the number of transverse arterioles did not change at approximately 440 per muscle (Fig. 4), resulting in a decrease in small arteriolar density as the muscle grew, even though there was an increase in the number of precapillary arterioles after maximal dilation with adenosine (Fig. 4), 3760 per muscle at 7 weeks vs 2381 per muscle at 4 weeks. Thus, we have shown that microvascular growth and development through the enlargement of preformed vessels. Moreover, precapillary arterioles are added to supply new capillaries.

The mechanism for the proliferation of precapillary arterioles during normal growth may be a metabolically related stimulus for angiogenesis. As the muscle grows, the capillaries become incapable of supplying enough oxygen and areas of hypoxia develop. This stimulates the growth of new capillaries, possibly through the release of angiogenic factors, such as basic fibroblast growth factor or adenosine. Capillaries form by budding from existing capillaries which in turn enlarge and take on a smooth muscle coat to form small arterioles.

As more capillaries develop and flow increases, the larger arterioles may be stimulated to grow by an endothelial mediated mechanism, either release of growth factors locally, or through chronic vasodilation. Although it may be possible for growth factors to diffuse from the venules to the larger arterioles, a more likely hypothesis is that growth factors act as paracrine or autocrine substances rather than circulating hormones. Alternatively, an increase in wall stress would result from vasodilation and this may be the stimulus for local growth of the arteriolar wall.

Reduced metabolic demand following orchidectomy resulted in a reduction in blood flow and an inhibition of growth of the microvessels. As a result, none of the arterioles significantly increased their diameter with age (Fig. 3) and the wall area of only the 1A showed an increase (Fig. 5). The wall area appears to be a function of arteriolar diameter (Fig. 6) whether the vessels are younger, older, or growth-inhibited. These findings are consistent with results of others which showed both a smaller diameter and less medial tissue mass caused by decreased blood flow in arteries of young animals (3, 8). These results are also concordant with previous experiments in which we treated one kidney-one clip hypertensive rats with captopril and found the same relationship between arteriolar internal diameter and cross-sectional wall area regardless of whether the animals were hypertensive, normotensive, or growth-inhibited (12).

The inhibition of vascular growth was also evident in the number of 4A's per 3A, which did not increase following orchidectomy (Fig. 4). These results could be explained by decreased concentrations of metabolic growth factors resulting from reduced metabolic activity of the cremaster. Initiators of arteriolar proliferation on the control side, such as hypoxia, were not present following orchidectomy. In spite of this inhibition of growth, arteriolar density (Fig. 7) was greater after orchidectomy than in the contralateral cremaster, because skeletal muscle growth is primarily responsible for the reduction in arteriolar density. Growth of the muscle is also responsible for the extension of the arcading network and thus the total length of 2As was also reduced (Fig. 4).

One hypothesis for the ability of blood flow to be sensed by the vascular wall and initiate structural changes is through the effect of shear stress on the endothelium (2,3). Consistent with this hypothesis, the bottom panel of Figure 2 shows that the diameter of the 1A was adjusted so that the shear rate at the wall was nearly the same regardless of the flow rate. Shear stress is dependent upon the shear rate and viscosity of the blood, which in turn is dependent on the hematocrit. Hematocrit decreases with decreasing vessel diameter, but Jendrucko and Lee (9) showed that the hematocrit in a 116 lm glass tube was reduced only 10% below the value of the feed reservoir hematocrit. In vivo, Lipowsky et al. (10) found that the hematocrit in a 60 lm arteriole was about 80% of that of systemic. In the present experiment, the 1A diameters in the control and orchidectomy sides were 138 lm and 103 lm respectively. It is therefore likely that the 1A hematocrit in both cremasters was similar and close to the systemic hematocrit. Thus, it can be assumed that the shear stress is also similar in the orchidectomy and control 1A's. This means that the arterioles accommodated themselves to the changes in flow in a manner consistent with maintaining constant shear stress. This is in agreement with several investigations that suggest that mean shear stress is the key parameter determining the size and growth of the arterial lumen (2,3).

In conclusion, these experiments show that arteriolar development during maturation in skeletal muscle primarily consists of increases in length, diameter, and wall mass of vessels already present in the younger animal. Only precapillary arterioles increase in number to supply the additional capillaries which also develop with age. Unilateral orchidectomy inhibited the growth of the arteriolar bed, including the formation of new precapillary arterioles. Flow-induced shear stress and/or local changes in growth factors are suggested as possible mechanisms mediating the alterations.

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Wang, DH.; Prewitt, RL.; (1998). Microvascular Adaptations to Reduced Blood Flow: Introduction of a New Model. Presented at INABIS '98 - 5th Internet World Congress on Biomedical Sciences at McMaster University, Canada, Dec 7-16th. Invited Symposium. Available at URL http://www.mcmaster.ca/inabis98/prewitt/wang0894/index.html
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