Microvascular rarefaction, defined by the anatomical loss of microvessels, is a common characteristic of hypertension. Because the loss of vessels accompanies elevated blood pressure therapies aimed at reversing rarefaction represent candidate treatments for the disease. However, the development of such therapies requires an understanding of the functional relationship between network patterns and microvascular resistance over the time course of aging and the identification of the molecular players responsible for the impaired network growth. Recent data by the PI suggests that microvascular networks in the adult spontaneously hypertensive rat have increased arterial/venous anastomoses indicating that rarefaction is more complex that just a loss of vessels. We also have observed reduced perivascular cell expression of Neuron-Glia Antigen 2 (NG2), a chondroitin sulfate proteoglycan functionally involved in angiogenesis. NG2 is a positive regulator of endothelial cell proliferation and migration and directly influences the number of vessels present. Our observations suggest a novel molecular meachanism for microvascular rarefaction during hypertension. We hypothesize that reduced NG2 expression in hypertensive microvascular networks results in altered architectural patterns leading to elevated microvascular resistance. In order to test this hypothesis, we will complete the following specific aims using the spontaneously hypertensive rat model:
AIM 1 : Determine the microvascular network architecture and NG2 expression alterations over the time course of aging in spontaneously hypertensive rats.
AIM 2 : Establish that NG2 inhibition is sufficient to alter microvascular network architectures.
AIM 3 : Use a computational model to quantitatively determine the effect of altered hypertensive microvascular network architectures on microvascular network resistance. The results from this work will set new directions for investigating the relationships between microvascular structure and elevated microvasuclar resistance in hypertension.
Elevated blood pressure in hypertension is associated with an age-related increase in microvascular resistance. Thus, design of hypertensive therapies aimed at reversing high blood pressure requires understanding how microvascular network architectures change over the time course of the disease, why microvascular network architectures change structure and the how network architectures influence resistance. The proposed work will serve to offer novel paradigms for investigating these questions.
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