Many abnormalities of bladder function, including diabetes mellitus, produce their effects due to disordered bladder smooth muscle contractility, abnormal growth regulation, and imbalances in remodeling of the ECM surrounding the smooth muscle. Our long-range goals are to develop an understanding of the mechanisms of control of these elements. We intend to investigate whether there is a common autocrine regulatory system based upon ANG II produced by bladder smooth muscle and interacting with locally produced growth factors and regulators of matrix remodeling. We hypothesize that these factors mediate complex cellular responses to mechanical activity of the bladder, and further, the abnormalities of these factors produce bladder dysfunction. Based upon analogies in the cardiovascular system and our own preliminary data, locally produced ANG II can mediate bladder contractility, smooth muscle cell growth and elements of the matrix remodeling regulatory balance. We, therefore, aim to: 1) determine the mechanisms of regulation of bladder contractility by ANG II using tissue baths. Mechanisms of contractile regulation by ANG II, its interactions with neural regulation, the regional distribution of these interactions within the bladder, and functional effects in vivo will be determined; 2) determine the mechanisms regulating bladder smooth muscle cell growth, with particular focus on growth stimulating mechanical forces; and 3) determine the role of mechanical stretch and autocrine angiotensin in the regulation of bladder extracellular matrix remodeling activity. We will examine whether autocrine cytokines are responsible for altered remodeling activity an modulation of degradative proteins and tissue inhibitors of metalloproteinases (TIMPs) in bladder smooth muscle. The significance of identifying and characterizing an autocrine regulatory system that affects bladder contractility, growth, and matrix remodeling that is linked with ANG II and mechanical forces, is the potential for pharmacologic manipulation which would likely involve specific modulation of factors that regulate the cellular response to ANG II. A mechanistic understanding of this potentially important system is essential. The broader implications of such an autocrine system are clear, as well, with potential for insight into other smooth muscle abnormalities.
