Although the influence of the renin angiotensin systems (RAS) in regulation of vascular structure has recently been emphasized by many investigators, little information exists as to the molecular events which link the angiotensin stimulus with growth responses in resistance vessels. The overall goal of this proposal is to investigate the functional and pathophysiologic significance of local and/or circulating angiotensin in arteriolar development and remodeling. Five specific hypotheses will be examined: 1. that an independent tissue angiotensin system exists in arterioles, 2. that gene expression of angiotensinogen and renin in arterioles is physiologically regulated, 3. that growth factors are involved in angiotensin-induced arteriolar growth, 4. that adrenergic receptors play an important role in the growth action of angiotensin II in arterioles, 5. that the local production of the trophic factor endothelin is stimulated by angiotensin. A component of these studies will be the development of a coherent model of the interaction between the circulating and tissue angiotensin systems and the description of the relationship between angiotensin and growth-related factors or genes. A combination of light microscopy and molecular biological techniques will be used to investigate these hypotheses. The proposed investigation will complement my previous in vivo studies of the microcirculation by allowing the integration of molecular events with previously documented physiologic phenomena. The information gained will enable us to more fully understand the growth regulation of microvessels and will provide insight into mechanisms by which the microvessels regulate their structure and function upon the activation of the RAS. Knowledge of these basic mechanisms will assist in interpreting the role of the RAS, especially the local vascular RAS, in normal microvascular development and in hypertension. Further, the studies should provide information necessary for the development of more specific inhibitors of angiotensin II production and the evaluation of therapeutic effectiveness of these inhibitors in hypertension.
| Nayak, Lalitha; Shi, Hong; Atkins, G Brandon et al. (2014) The thromboprotective effect of bortezomib is dependent on the transcription factor Kruppel-like factor 2 (KLF2). Blood 123:3828-31 |
