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Introduction: Hypertension is a major risk factor for cardiovascular diseases including cardiac hypertrophy, stroke, and heart failure. Hypertension accelerates arterial stiffening noted with natural aging. Aortic stiffness has been shown to be both a cause and a consequence of isolated systolic hypertension. Thus, it is of high clinical interest to target arterial stiffening in the context of hypertension. We have previously identified lysyl oxidase-like 2 (LOXL2) as a potential therapeutic target for treating vascular stiffening. LOXL2 is a key enzyme in the extracellular matrix that catalyzes matrix deposition and remodeling. We have previously shown that LOXL2 depletion decelerates arterial stiffening during natural aging by modulating matrix remodeling and smooth muscle cell stiffness and contractility. Our hypothesis in this study is that LOXL2 depletion is protective against hypertension induced arterial stiffening, and this was determined via the established angiotensin II (Ang II) infusion model of experimental hypertension in LOXL2+/- mouse model. Methods and results: Ang II pumps were implanted in LOXL2+/- and WT mice for a 3-week treatment. Blood pressure and pulse wave velocity were measured noninvasively to assess hypertension and aortic stiffness. Results corroborated that Ang II infusion induced hypertension in WT and LOXL2+/- mice, and that arterial stiffening was ameliorated in LOXL2+/- mice even when Ang II-induced hypertension was present. Uniaxial tensile testing was used to test the elastic properties of the aortic rings, and wire myography was used to test their vasoreactivity. These experiments showed that the increase in arterial stiffness due to Ang II-induced hypertension was driven by both matrix remodeling and VSMC response. Histological analysis supported these findings, showing increased aortic wall thickness, interlamellar distance and collagen deposition with Ang II infusion. Elevated heart weight in mice with Ang II infusion and qPCR results revealed induced cardiac hypertrophy, which was not protected by LOXL2 knockdown. Moreover, human aortic SMC and endothelial cells were cyclically stretched, to show that the overexpression of LOXL2 in the aorta under Ang II-induced hypertension is upregulated by cyclic strain. Conclusion: Arterial stiffening is increased with Ang II infusion; however, it is ameliorated in LOXL2+/- mice compared to WT despite the development of Ang II-induced hypertension. This rise in arterial stiffness is driven by both matrix remodeling and VSMC response. Cardiac hypertrophy occurred with Ang II infusion and LOXL2 knockdown was not protective against it. Future studies will continue to 1) elucidate the mechanisms involved in the regulation of LOXL2 expression in response to Ang II-induced hypertension, 2) investigate the sex differences in in vivo stiffness and vasoreactivity, and 3) study LOXL2 as a potential therapeutic target against cardiac hypertrophy. Private foundation grant: NHLBI grant R01HL148112 01 (L.S.) This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.