| dc.description.abstract | Hypertension is a significant risk factor for cardiovascular diseases and a leading cause of worldwide morbidity and mortality. Dysregulation of intracellular Ca2+ in vascular smooth muscle (VSM) cells is one major contributor to the development of vascular hypercontractility and remodeling in hypertension. Plasma membrane (PM)-localized large-conductance, Ca2+-activated K+ (BKCa) channels prevent hypercontractility through membrane hyperpolarization in response to vasoconstrictor-induced activation of inositol trisphosphate receptors (IP3Rs), localized on the sarcoplasmic reticulum (SR). However, loss of close contact or coupling between BKCa and IP3R may diminish the BKCa-mediated protection against hypercontractility and hypertrophy and contribute to the development of hypertension. The overall goal of this study was to understand the role of BKCa-IP3R coupling in the development of vascular hypercontractility and remodeling. I used a hypertensive animal model, spontaneously hypertensive rat (SHR), to study the impact of the loss of this coupling. My hypothesis was that there is a loss of communication between the IP3 receptors and the BKCa channels in SHR VSM cells leading to reduced BKCa current after IP3R activation.
My first objective was to determine the role of functional coupling of BKCa and IP3R in vascular hypercontractility and hypertrophy development. Based on the findings, one can conclude that in SHR mesenteric VSM cells, there is a loss of functional IP3R-BKCa coupling, and it might be involved in vascular hypercontractility and hypertrophy.
My second objective was to examine and compare the molecular coupling of BKCa and IP3R between normotensive and hypertensive rats. My data suggest that the molecular connection between BKCa and IP3R is disrupted in SHR VSM cells. My results also suggest that this loss of connection is not due to downregulation of junctophilin-2 (JPH2) but may be due to defective tethering of JPH2 to the PM.
Together, this research provides an improved understanding of the crucial roles played by BKCa-IP3R coupling in hypertension. An understanding of ion channel coupling under disease conditions may provide relevant caveats where BKCa channels are considered a therapeutic target. I expect that the knowledge gained from my studies will fundamentally advance the field of ion channel-based therapeutics, especially in cardiovascular disorders. | en_US |
