Background: Hypertension accelerates arterial stiffening associated with natural aging. Aortic stiffness is both a cause and a consequence of isolated systolic hypertension. We identified lysyl oxidase-like 2 (LOXL2), a key matrix remodeling enzyme, as a potential therapeutic target for treating vascular stiffening. Here, we determine if LOXL2 depletion is protective against hypertension induced arterial stiffening, and we elucidate the sex differences present.
Methods: Angiotensin II (Ang II) pumps were implanted in Loxl2 +/- and WT mice. Blood pressure and pulse wave velocity were measured noninvasively to assess hypertension and aortic stiffness. Wire myography and uniaxial tensile testing were used to test aortic vasoreactivity and elastic properties. Histological analysis and Western blotting determined vascular wall properties. The effect of biomechanical strain on LOXL2 expression and cell alignment was determined via uniaxial cell stretching.
Results: Ang II infusion induced hypertension in WT and Loxl2 +/- mice, and arterial stiffening was ameliorated in Loxl2 +/- male mice. LOXL2 depletion protected males from Ang II mediated potentiation of vasoconstriction, and attenuated passive arterial stiffening. Histological analysis showed increased aortic wall thickness and intralamellar distance with Ang II. Western blotting revealed an increase of LOXL2 accumulation and processing in hypertensive mice. Increased cyclic strain contributed to upregulation of LOXL2 in the aorta with induced hypertension.
Conclusions: Arterial stiffening is increased with Ang II infusion; however, it is ameliorated in Loxl2 +/- male mice compared to WT despite developing Ang II-induced hypertension. This rise in arterial stiffness is driven by both VSMC response and matrix remodeling.