VASCULAR SMOOTH MUSCL ADRENOCEPTOR FUNCTION & EXPRESSION

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We have recently found that up to 4 different alpha-adrenoceptor (AR) subtypes may be expressed by vascular smooth muscle cells (SMCs), that the array of subtypes differs between artery and vein, and that certain conditions may induce expression of a normally repressed subtype. Little is known concerning regulation of expression of these different alphaARs by SMCs. Moreover, all of the subtypes present may not mediate contraction & their other SMC functions are unclear. While elevated catecholamine activity promotes SMC growth & is a risk factor for atherosclerosis & hypertensive hypertrophy little is known about how alphaARs regulate SMC growth and the alphaAR subtypes involved. The hypotheses to be tested are that: (1) A specific alphaAR subtype(s) modulates SMC growth and expression of contractile & structural proteins, thereby linking sympathetic state to SMC growth & differentiation. (2) Fundamental signals in the vascular wall microenvironment, ie., catecholamines, oxygen and pressure-induced cell stretch regulate expression of specific alphaAR subtypes. The following aims will be examined in rat aorta SMCs in cell culture and in situ in the vascular wall. Aim 1 examines the effect of stimulation of different alphaAR subtypes on growth and gene expression (mRNA & protein) of alpha- and beta-actin. Aim 2 determines the influence of stimulation of each subtype on expression of the cognate & other alphaAR subtypes. Aim 3 investigates regulation of alphaAR expression by oxygen. Aim 4 examines the effect of cell stretch (pressure) on alphaAR expression. Aim 5 determines involvement of changes in gene transcription rate (nuclear runoff), mRNA stability, and DNA & protein synthesis in the altered expression of actins, alphaAR subtypes and SMC growth induced by alphaAR stimulation, tissue oxygen and cell stretch. Aim 6 tests the hypothesis that an O/2- binding heme protein & sequences in the alpha1B-AR gene mediate hypoxia stimulation of alpha1B expression. These studies will yield insight into a perplexing fundamental question, namely why SMCs express multiple alphaAR subtypes and how expression of the subtypes is regulated. The findings could open up new opportunities in the study and understanding of vascular hypertrophic diseases by establishing linkage among catecholamines, ischemia, blood pressure and expression of specific alphaAR subtypes that modulate SMC growth. In addition, these studies will identify how intravascular pressure and tissue oxygen influence the pattern and density of alpha-adrenergic receptor subtypes expressed by vascular smooth muscle.