MMP12 as a Mediator of Arterial Stiffening

Loss of elasticity in blood vessels is an important aspect of aging, as it creates hypertension and cardiovascular remodeling that ultimately leads to heart disease and death, along the way increasing the damage done by blood vessel failure in the brain as well as raising the risk for many other age-related conditions. Arterial stiffening is thought to be caused by cross-links and calcification, alterations in the extracellular matrix that degrade its structural properties. It is worth assuming that nothing in biology ever has one cause or a simple set of contributing mechanisms, however. Researchers here provide evidence for increased levels of the enzyme matrix metalloproteinase-12 (MMP12) to be significantly involved in arterial stiffening, though the underlying root cause of that increase remains an open question:

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 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.



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