Cardiovascular disease remains the leading cause of morbidity and mortality in the aging US population. Although vascular dysfunction in the aging population has clearly been demonstrated, the exact mechanism(s) underlying this dysfunction remain unclear. Aged rats have been demonstrated to have elevated arterial wall Ca2+ and pressure-induced constriction in isolated cerebral arteries (CA). It has been suggested that much of this dysfunction may be due to a decrease in nitric oxide (NO) or downstream products of the NO pathway. Yet, altered NO signaling does not explain altered Ca2+ handling and vascular dysfunction observed in aged rats. Furthermore, there is little data investigating altered vascular function in the microvasculature. Novel data from our laboratory indicate that growth hormone (GH) treatment of aged rats (OGH; 28-33 months) attenuates age-associated increases in vascular tone in resistance-sized vessels from the cerebral circulation. Our data further suggest that the mechanisms underlying this elevation in vascular tone include a decrease in nitric oxide (NO) and prostacyclin (PGI2)-mediated dilation, and an increase in thromboxane (Tx)/prostaglandin H2 (PGH2)-mediated constriction, dysfunctions that are reversed by GH therapy. We hypothesize that age-associated alterations in the function/expression of nitric oxide synthase (NOS) or cyclooxygenase (COX) isoforms promotes changes in vascular tone, membrane potential (Em), and arterial wall Ca2+ in aged Fisher 344XBN rats. Furthermore, we hypothesize that GH treatment reverses the age- dependent changes in Em, Ca2+ handling and vasoreactivity by reestablishing NOS- and COX-dependent signaling and function comparable to that seen in younger animals. Accordingly, we propose the following specific aims:
Specific Aim 1. Determine the relative contribution of NOS function to altered vascular tone, Em, and arterial wall Ca2+ in old and old-GH treated rats.
Specific Aim 2 : Determine the relative contribution of COX-1 and COX-2 products to altered vascular tone, Em and arterial wall Ca2+ in old and old-GH treated rats. We believe that these studies will increase our understanding of aging and result in new and important findings that may lead to the development of therapeutic approaches to reverse and/or delay aging-associated cerebral vascular dysfunction/disease, thus improving the quality of life for the aging population. ? ? ? ?
