Hypertension is a serious and prevalent disease. Current dogma states that the pathogenesis of hypertension requires abnormal renal sodium handling as the 'final common pathway'. The fundamental hypothesis being tested in this Program Project Grant (PPG) is that loss of the normal function of VSMC regulatory proteins can directly cause vascular diseases such as hypertension. We recently identified vascular dysfunction and associated hypertension in several genetically modified mice deficient in or expressing abnormal forms of VSMC contractile regulatory proteins. These mice lack gross abnormalities of renal function. Based on these observations we propose to test the hypothesis that hypertension can result from primary abnormalities of vascular smooth muscle cell function. Three of these hypertensive mouse lines will be studied in each of 3 specific aims: (1) protein kinase G Ialpha(PKGIalpha) leucine zipper mutant 'knock-in' (LZM KI) mice, which express a mutant PKGIalpha protein lacking a functional leucine zipper domain, (2) regulator of G protein signaling 2 knockout (RGS2KO) mice, and (3) estrogen receptor beta knockout (betaERKO) mice. We will explore the relationship between vascular dysfunction and hypertension in each of these mouse lines by examining the effects of transplantation of kidneys to and from the hypertensive mice and their wild type littermates, on blood pressure, vascular function, and renal function. For each gentotype, four groups of mice will studied: Group 1. hypertensive mice transplanted with a kidney from a hypertensive donor, Group 2. hypertensive mice transplanted with a kidney from a wild type littermate, Group 3. normotensive wild type mice transplanted with a kidney from another wild type mouse, and Group 4. wild type mice transplanted with a kidney from a hypertensive, genetically-altered mouse. Groups 1 and 3 will serve as controls for the transplant procedure, whereas comparison of the effects of transplantation on blood pressure, vascular function, and renal function in the mice in Groups 2 and 4 will reveal the relative contribution of the vascular dysfunction vs. any renal abnormalities to the hypertensive phenotype. Direct testing of our hypothesis, as proposed here, is of central importance to the conceptual framework upon which current approaches to the diagnosis and treatment of disorders of blood pressure are based. As such, these studies have the potential to advance our ability to diagnose and treat hypertension.
Showing the most recent 10 out of 40 publications
