Matrix metalloproteinase-12 is an essential mediator of acute and chronic arterial stiffening

Abstract

Arterial stiffening is a hallmark of aging and risk factor for cardiovascular disease, yet its regulation is poorly understood. Here we use mouse modeling to show that matrix metalloproteinase-12 (MMP12), a potent elastase, is essential for acute and chronic arterial stiffening. MMP12 was induced in arterial smooth muscle cells (SMCs) after acute vascular injury. As determined by genome-wide analysis, the magnitude of its gene induction exceeded that of all other MMPs as well as those of the fibrillar collagens and lysyl oxidases, other common regulators of tissue stiffness. A preferential induction of SMC MMP12, without comparable effect on collagen abundance or structure, was also seen during chronic arterial stiffening with age. In both settings, deletion of MMP12 reduced elastin degradation and blocked arterial stiffening as assessed by atomic force microscopy and immunostaining for stiffness-regulated molecular markers. Isolated MMP12-null SMCs sense extracellular stiffness normally, indicating that MMP12 causes arterial stiffening by remodeling the SMC microenvironment rather than affecting the mechanoresponsiveness of the cells themselves. In human aortic samples, MMP12 levels strongly correlate with markers of SMC stiffness. We conclude that MMP12 causes arterial stiffening in mice and suggest that it functions similarly in humans.

Distal vessel stiffening is an early and pivotal mechanobiological regulator of vascular remodeling and pulmonary hypertension

“…As our AFM measurements were made at room temperature in nonperfused tissue, the measured tissue stiffness does not take into account active cellular contributions, as well as possible contributions from changes in transmural distending pressure (67) or vascular flow. However, as this study focused on distal PA stiffness, we suspect that flow and transmural pressure contributions to stiffness are small and that our measurements capture changes in vascular wall stiffness associated with ECM remodeling (68). Additional limitations of AFM include sampling challenges associated with the small spatial scale of measurements and inherent biological heterogeneity across and within vessels.…”

Arterial Stiffness: Different Metrics, Different Meanings

“…As expected, the numerical implementation is straightforward. Nevertheless, results from AFM for assessing vascular cell stiffness [25,26] and arterial properties [27][28][29][30] typically have been interpreted in terms of a single Young's modulus inferred from the Hertz solution, which tacitly ignores the important nonlinear dependence on in-plane prestretch and the nonlinear (often exponential) material behavior. Hence, the inferred values of stiffness are typically well below in vivo values and could be misleading regarding in vivo mechanobiology.…”

Cardiovascular protection in females linked to estrogen-dependent inhibition of arterial stiffening and macrophage MMP12

“…We previously described an important role for MMP12, a potent elastase (17,18), in arterial stiffening with age and in the response to vascular injury in mice (19). Although the MMP12 effect on aging-and injury-associated arterial stiffening was attributed primarily to its expression by vascular smooth muscle cells (SMCs) (19), the role of MMP12 in animal models of atherosclerosis has more commonly been associated with its expression by macrophages (20)(21)(22). Additionally, work by Johnson et al (23) suggests a Arterial stiffening is a consequence of aging and a cholesterol-independent risk factor for cardiovascular disease (CVD).…”