Tissue transglutaminase as a therapeutic target for arterial stiffening and hypertension in obesity

/ABSTRACT Arterial stiffening and microvascular inward remodeling are early and independent predictive risk factors of cardiovascular disease (CVD) and mortality. In obesity, these risk factors occur early, preceding and contributing to the development of hypertension and organ dysfunction. However, despite CVD being the primary cause of mortality in individuals with obesity, no treatments are currently available for obesity- associated vascular stiffening and remodeling. This is due, in part, to an unclear understanding of the underlying mechanisms for these common conditions. Rigorous published research and preliminary studies indicate that vascular smooth muscle cell (SMC) tissue transglutaminase (TG2) is increased in obesity and that TG2 activity contributes to arterial stiffening and microvascular inward remodeling. However, the mechanisms by which obesity increases TG2 activity, how TG2 promotes arterial remodeling and contributes to hypertension development, and whether TG2 could be targeted therapeutically to reduce CVD in obese patients remain unclear. This proposal addresses those significant gaps in knowledge. The central hypothesis of this proposal is that obesity-associated SMC TG2 upregulation and mechanosensation increase arterial collagen crosslinking, actin polymerization, and myogenic tone, contributing to vascular stiffening and hypertension. A corollary to this hypothesis is that treatment with the novel TG2-specific inhibitor, ZED3641, will attenuate arterial stiffening and blood pressure in obese-hypertensive pigs. This innovative hypothesis will be tested with gain- and loss-of-function genetic manipulation and pharmacological experiments in cultured vascular SMC and isolated arteries, in animal models of SMC-specific MR and TG2 deletion, and in obese- hypertensive pigs. Specifically, studies in Aim 1 will determine the mechanism of SMC mineralocorticoid- dependent regulation of TG2 in obesity. In Aim 2, the role of TG2 mechanosensation in arterial stiffening, myogenic vasoconstriction, and remodeling in obesity will be determined. Finally, studies in Aim 3 will determine the arterial de-stiffening effects of TG2 inhibition in isolated arteries from obese patients and in a swine model of obesity and hypertension. It is posited that targeting TG2 activity holds extraordinary promise for correcting arterial stiffening, remodeling, and hypertension in obese patients, thus reducing their CVD burden. Project Number: 1R01HL181939-01 | Fiscal Year: 2025 | NIH Institute/Center: National Heart Lung and Blood Institute (NHLBI) | Principal Investigator: Luis Martinez-Lemus (+2 co-PIs) | Institution: UNIVERSITY OF MISSOURI-COLUMBIA, COLUMBIA, MO | Award Amount: $685,654 | Activity Code: R01 | Study Section: Special Emphasis Panel[ZRG1 IVBH-G (02)] View on NIH RePORTER: https://reporter.nih.gov/project-details/1R01HL18193901