Gregory Dale Fink - US grants

Project Summary/Abstract - Core A The Administrative Core guides and supervises the overall Program Project research effort. The Director has ultimate responsibility for supervision of Program Project activities. The Director is assisted by the Co-Director. An important function of the Core is to organize and schedule bi-monthly meetings of all Program Project personnel, and maintain written records of these meetings. Frequent meetings documented with reports presented by Project and Core Leaders ensure that all projects are meeting Program goals. Project and Core Leaders meet separately once a month to discuss progress, trouble-shoot scientific or technical issues and make policy decisions. Electronic records of all group meetings are available to Program personnel through a Program Project Electronic Group (ANGEL.msu.edu). The Administrative Core communicates with the Internal and External Advisory Committees. These committees monitor Program Project research progress and provide evaluations and critiques of the group effort. They also assist the Director in developing solutions to any research-related problems that may arise. The Administrative Core is responsible for monitoring Program expenditures, including travel by Project Leaders, and routine bookkeeping. A majority of publication costs arising from Program Project-funded research will be processed through individual projects. Finally, this Core handles assembly and submission of annual progress reports.

Project Summary/Abstract - Core B This core unit serves as a central resource for all control (C) and high fat (HF) fed animals used by all investigators in the Program Project. Core personnel are responsible for continuing and up-to-date assessment of animal requirements for all Projects. They ensure timely ordering, delivery, and proper housing of animals. All animal surgery (except some post-mortem tissue removal) is conducted and/or supervised by Core B personnel. This includes production of HF feeding induced hypertension and appropriate control or sham- operated rats, most routine tissue removal for in vitro analysis, and instrumentation of rats for chronic hemodynamic monitoring. All animals used in the Program Project have their blood pressure carefully and reliably quantified by Core B personnel either directly (implanted arterial catheter or radiotelemetry transmitter) or indirectly (systolic pressure by tail-cuff sphygmomanometry) prior to or as part of each experimental protocol. Daily animal husbandry, health surveillance and record keeping also are the responsibility of Core B personnel, in association with the staff of University Laboratory Animals Resources (ULAR) of Michigan State University. Core B personnel also are responsible for developing and implementing new physiological techniques for evaluating cardiovascular function in rats. A major advantage of the Animal Core is that it facilitates the most efficient use of animals by Program Investigators. Our in vivo protocols also are designed to maximize the amount of data collected from a single animal. This is achieved through use of long-term repeated measurements of cardiovascular parameters where possible, rather than studying separate groups of rats at each time point of interest. At the end of chronic in vivo protocols, tissue samples from the rats are distributed to one or more Program investigators for further study.

DESCRIPTION (provided by applicant): Overall Hypertension is a major risk factor for premature death and disability in the United States. New approaches to therapy are needed to improve clinical management and reduce mortality and morbidity. Our Program Project is based on the assumption that redistribution of peripherally stored blood toward the heart via changes in vascular capacitance is an important factor in the pathophysiology of hypertension. Since most peripherally stored blood is in the splanchnic veins, redistribution is driven largely by reduced splanchnic venous capacitance. This can be caused by active constriction of splanchnic arteries, or active or passive constriction of splanchnic veins. Over the past five years our Program Project has focused on characterizing sympathetic neural mechanisms that regulate venous capacitance, with emphasis on differential control of arterial and venous function. Most of our work has been conducted in rodents with mineralocorticoid-salt hypertension. However, clinical hypertension is increasingly associated with obesity and especially with accumulation of inflamed visceral fat in the splanchnic region. Combined with evidence of sympathetic overactivity in obesity, this led us to hypothesize that altered sympathetic control of splanchnic arteries and veins could be a critical link between obesity and hypertension. Therefore, recently we have begun to refocus our work on a high fat feeding model of obesity-related hypertension in rodents and on complementary studies in splanchnic blood vessels and fat obtained from human patients. Over the next five years we propose to: 1) perform in vivo physiological studies in our rodent model to determine the amount, source and impact on arterial pressure of splanchnic sympathetic drive in obesity-related hypertension; 2) examine in rat and human blood vessels how inflamed visceral fat impacts sympathetic neurotransmission; and 3) establish in rat and human blood vessels the importance of both a) sympathetic drive to perivascular adipose tissue and b) a newly discovered adrenergic system endogenous to perivascular adipose tissue itself.

Project Summary/Abstract ? Project 1 Previous animal-based experiments in this Project focused on the impact of vascular capacitance (blood storage) on cardiovascular regulation. Because the splanchnic vasculature plays a large role in determining overall vascular capacitance, and the sympathetic nervous system is the major regulator of splanchnic vascular capacitance, we investigated the idea that the splanchnic sympathetic nerves may be important in hypertension. Obesity is now known to be the major cause of human hypertension and its accompanying morbidities, mortalities and increased health care costs. Furthermore, increased sympathetic nervous system activity is accepted as one critical link between obesity and hypertension. Although sympathetic control of the kidney is an established factor in obesity-related hypertension, there is substantial evidence that sympathetic activity to other targets also plays a part. Given the close association of obesity-related sympathetic overactivity and hypertension with accumulation of inflammed adipose tissue specifically in the splanchnic region (visceral adipose tissue), we hypothesize that splanchnic sympathetic activity is important in obesity- associated hypertension. We further propose that splanchnic sympathetic activity regulates arterial pressure in obesity not only by affecting the function of splanchnic blood vessels, but also by promoting and accelerating inflammation of the visceral adipose tissue surrounding those blood vessels. In this context, splanchnic sympathetic activity refers not only to effects of sympathetic nerves and circulating catecholamines, but also to norepinephrine released from a newly discovered adrenergic system intrinsic to visceral fat itself (described in Project 3).To test these hypotheses, experiments will be conducted in rats made obese by feeding them a high fat (HF) diet for up to 26 weeks, starting at 3 weeks of age. The rats will develop glucose intolerance, visceral obesity and hypertension starting between 12-18 weeks of the diet. At 6, 18 and 26 weeks of HF feeding we will estimate splanchnic nerve activity using norepinephrine spillover; measure vascular capacitance (mainly splanchnic), splanchnic vascular resistance and their dependence on adrenergic input; and evaluate the impact of chronic denervation of splanchnic blood vessels and visceral adipose tissue on hypertension development. Finally, we will determine if prostaglandin D2 in the brain contributes to sympathoexcitation in our rat model of obesity. It is anticipated that these studies could produce new approaches to managing obesity-related hypertension.

Project Summary Despite intensive investigation, disorders of blood pressure regulation -- both hypertension and hypotension -- continue to be serious, widespread and intractable medical problems. Relatively few effective approaches to management of blood pressure dysregulation have emerged over the last few decades so novel strategies are needed. Serotonin (5-hydroxytryptamine, 5-HT) was first discovered in the cardiovascular system, but the roles of endogenous 5-HT in cardiovascular physiology and pathophysiology are not well defined. This is because 5-HT has complex effects within the CV system that are mediated by several distinct receptor subtypes. This is well-illustrated when considering the endpoint of blood pressure. Depending on the site of injection, the dose administered, and the receptor targeted, serotonergic drugs can raise or elevate blood pressure. Of the 5-HT receptors expressed in the CV system (the 5-HT 1B/1D, 5-HT2A, 5-HT3, 5-HT4 and 5- HT7 receptor), 5-HT has the highest affinity for the 5-HT7 receptor. Since endogenous plasma and tissue levels of 5-HT are estimated to be in the low nM range, endogenous 5-HT likely acts primarily at 5-HT7 receptors to effect changes in blood pressure. Previous studies support this conjecture regarding the acute (seconds to minutes) effects of exogenous 5-HT. Over the last decade, we have proven this is also true for the chronic (days to weeks) blood pressure effects of exogenous 5-HT, using both traditional pharmacological approaches and a new genetic model (5-HT7 receptor knockout rat) that we developed. Therefore, we now are well-positioned to test the overall hypothesis that endogenous 5-HT modifies blood pressure in normal and pathophysiological conditions primarily by activation of 5-HT7 receptors in the peripheral vasculature, with the ultimate goal of capitalizing on 5-HT7 receptor pharmacology to treat disorders of blood pressure regulation. We propose to test this hypothesis via three Specific Aims: Aim 1: To test the hypothesis that 5-HT7 receptor activation dilates the microcirculation; Aim 2: To test the hypothesis that the vascular 5-HT7 receptor is (constitutively) activated endogenously to lower blood pressure in normal rats; and Aim 3: To test that the hypotension created in rat models with increased release or formation of 5-HT is 5-HT7 receptor-dependent. An integrated series of techniques that are the strengths of our combined laboratories are proposed. These include isolated tissue bath measurement of isometric contraction, measures of receptor activation that include the concept of constitutive activity, and radiotelemetry to measure cardiovascular parameters in conscious rats. Our established expertise is combined with newly gained abilities to image splanchnic venous and arterial diameters in the whole rat. This project is aimed to discover the unique ability of 5-HT to selectively activate the venous (and possibly micro) circulation through the 5-HT7 receptor and reduce blood pressure, a promising therapeutic lead for numerous cardiovascular disorders.