Macdonald, Justin AnthonyTurner, Sara Rose2018-10-042018-10-042018-09-19Turner, S. R. (2018). Novel Regulators of Vascular Myogenic Tone: A Focus on SMTNL1 and ZIPK (Doctoral thesis, University of Calgary, Calgary, Canada). Retrieved from https://prism.ucalgary.ca. doi:10.11575/PRISM/33116http://hdl.handle.net/1880/108764Myogenic constriction in the resistance vasculature plays a fundamental role in the regulation of blood flow, maintenance of mean arterial pressure and in promoting overall cardiovascular health. Myogenic control of these arteries is an innate function of the vascular smooth muscle and is activated by pressure-dependent mechanisms of Ca2+-CaM-MLCK activation, Ca2+ sensitization and cytoskeletal reorganization. Recently, two proteins of interest to our research group were found to contribute to Ca2+ sensitization in vascular smooth muscle, smoothelin-like 1(SMTNL1) and zipper-interacting protein kinase (ZIPK). SMTNL1 is a relatively unknown protein which may act as an inhibitor of MLCP. ZIPK is a Ser/Thr kinase capable of phosphorylating LC20, MYPT1 and CPI-17 proteins among other targets. Neither SMTNL1 nor ZIPK has been previously investigated for a role in contributing to the regulation of the vascular myogenic response, and this investigation forms the core of this thesis. The findings presented here identify: (1) enhanced myogenic response in the mesenteric arteries of the male SMTNL1 KO mouse corresponding with (2) significant potential for Ca2+ sensitization via down regulation of MYPT1 and upregulation of CPI-17, and (3) the first evidence for ZIPK contribution to the vascular myogenic response of the rat cerebral and cremasteric arteries. While these findings were limited to the healthy vasculature, common chronic diseases such as hypertension and type 2 diabetes mellitus are known to be associated with pathological alterations in the myogenic response of the vasculature. Using a novel and specific ZIPK inhibitor, HS38, we identified a role for ZIPK activity in mediating some of the maladaptations of the vasculature in rodent models of hypertension (the SHR) and type 2 diabetes (the GK rat). In summary, these findings suggest both SMTNL1 and ZIPK play important roles in the regulation of healthy vascular function and may provide new avenues for exploration into the dysfunction of the vasculature in pathological conditions.engUniversity of Calgary graduate students retain copyright ownership and moral rights for their thesis. You may use this material in any way that is permitted by the Copyright Act or through licensing that has been assigned to the document. For uses that are not allowable under copyright legislation or licensing, you are required to seek permission.Smooth Muscle PhysiologySMTNL1ZIPKMyogenic ResponseAnimal PhysiologyBiology--MolecularBiochemistrydoctoral thesis10.11575/PRISM/33116