In vivo, small, resistance-size arteries exist in a partially contracted state from which stimuli can cause constriction or dilation to modulate regional blood flow and systemic pressure. Several vasoactive stimuli, including acetylcholine (ACh) and intraluminal flow act through endothelial cells (ECs), yet mechanisms by which the endothelium senses flow and transduces this signal to dilation are poorly understood. ECs express polycystin 1 (PKD1) and polycystin 2 (PKD2). Evidence suggests that PKD1 and PKD2 may form a flow-sensing complex in kidney epithelial cells and in recombinant expression systems. PKD2 is a member of the transient receptor potential (TRP) family of non-selective cation channels, whereas PKD1 is not a channel. Investigating physiological functions of PKD1 and PKD2 in native ECs is challenging as both of these proteins are expressed in multiple arterial wall cell types, including ECs and smooth muscle cells (myocytes) and specific pharmacological modulators do not exist. For this proposal we generated novel, inducible, EC-specific PKD1 (PKD1 ecKO) and PKD2 (PKD2 ecKO) knockout mice to examine physiological functions of these proteins. Using these mice to generate preliminary data, we propose the novel hypothesis that an increase in fluid flow in arteries stimulates PKD1 and PKD2 to physically interact with each other in ECs and that this process causes vasodilation and a reduction in systemic blood pressure. We anticipate that this research will accrue mechanistic data that will increase our knowledge of the physiology and pathophysiology of blood pressure regulation. This may ultimately lead to the development of novel approaches to reduce blood pressure in patients and to reduce the incidence of cardiovascular disease in humans.
|Program type||Postdoctoral Fellowship|
|Effective start/end date||01/01/2020 → 12/31/2021|