In the past decade, work supported by this grant has found that norepinephrine (NE) induces growth of smooth muscle cells (SMCs) and adventitial fibroblasts in vitro and in vivo. This growth factor-like activity, con- firmed by others, is accentuated in arteries undergoing hypertrophic changes in pathologic (e.g., balloon injury) and adaptive physiologic settings (e.g., flow remodeling), even at baseline levels of sympathetic tone. The responsible 11-adrenoceptor (AR) type differs from the one that generally mediates constriction. Major findings during the previous grant period were: (1) Adrenergic-induced growth is generalized to other settings besides injury, e.g., intimal hyperplasia in pulmonary hypertension, collateral wall thickening, and low-Flow Induced Negative (inward) hypertrophic Remodeling (FINR). (2) The key signaling elements were identified: 11-AR AE NAD(P)H-oxidase AE ROS/H2O2 AE pro-HB-EGF-cleavage AE HB-EGF AE EGFR AE Raf1 AE MEK AE ERK1/2 AE cell hypertrophy, proliferation and migration, collagen accumulation, thickening of intima, media and adventitia. Not only do these findings have potential relevance to disease, but they also attach a function to particular 11- AR subtypes present on SMCs and adventitial fibroblasts that until now had not been ascribed a function. Possible support for this mechanism in humans has recently appeared;chronic treatment of prostatic hypertrophy with an 11A-AR antagonist was accompanied by a 72% reduction in the development of symptoms of atherosclerosis-induced ischemic heart disease (reviewed in Section 4). Thus, it is now important to determine if this trophic pathway exists in human vessels and if it contributes to or worsens atherogenesis (Aims I &II). Although HB-EGF is a major regulator of epithelial growth, wound healing and cancer, little is known about its role in vascular wall cells. Complimenting the above findings, our preliminary work for Aim III has obtained intriguing evidence that HB-EGF may serve as a general signaling nexus in vascular wall growth. For example, we find HB-EGF is required for both adrenergic growth and FINR-- a model with some features common to atherogenesis. While ECs, SMCs and macrophages release HB-EGF in vitro, whether they do in vivo is un- known (Aim III). These studies are requisite to Aim IV which will test the novel hypothesis that ROSAEHB-EGF signaling is important in atherosclerosis. These studies continue the long-term goal of this project to better understand the regulation of vascular wall growth and remodeling in adaptive conditions and vascular disease.
While acute increases in catecholamines (adrenalin and noradrenaline) act beneficially to constrict blood vessels and strengthen the heart's activity in exercise and stressful situations, continuously high levels are induced by risk factors for vascular disease (e.g., chronic stress, aging, high salt diet, diabetes, obesity, smoking, male sex, hypertension, and sedentary lifestyle). This project seeks to extend our previous investigations in rodents, which have shown that chronic increases in catecholamines have growth factor-like (trophic) actions that may contribute to or worsen vascular disease (e.g., atherosclerosis, arteriosclerosis, restenosis and bypass graft failure), into studies that may lead to new treatments to block this pathway in human vascular disease. Thus, we will study human vessels to: 1) examine if catecholamines are trophic, especially those with early signs of vascular disease, 2) identify the responsible cellular signaling mechanisms, and 3) also conduct studies in rats and mice to better understand the signaling mechanisms (in particular HB- EGF), test whether catecholamines and HB-EGF worsen experimental atherosclerosis, and see if we can lessen disease in animal models by blocking these signaling components.
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|Wang, Shiliang; Zhang, Hua; Dai, Xuming et al. (2010) Genetic architecture underlying variation in extent and remodeling of the collateral circulation. Circ Res 107:558-68|
|Zhang, Hua; Prabhakar, Pranay; Sealock, Robert et al. (2010) Wide genetic variation in the native pial collateral circulation is a major determinant of variation in severity of stroke. J Cereb Blood Flow Metab 30:923-34|
|Chalothorn, Dan; Faber, James E (2010) Strain-dependent variation in collateral circulatory function in mouse hindlimb. Physiol Genomics 42:469-79|
|Chalothorn, Dan; Zhang, Hua; Smith, Jennifer E et al. (2009) Chloride intracellular channel-4 is a determinant of native collateral formation in skeletal muscle and brain. Circ Res 105:89-98|
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