MOLECULAR DRIVERS OF VASCULAR REMODELING


Zorina Galis, Ph.D., Division of Cardiovascular Sciences, NIH, Bethesda, MD, USA

During their natural history, blood vessels undergo enduring, and sometimes irreversible structural changes in size and composition, a process commonly referred to as vascular remodeling. Many of these changes are initiated as a physiological response allowing adaptation and repair of the vessel wall, however inappropriate remodeling underlies the pathogenesis of major cardiovascular conditions, such as atherosclerosis, hypertension, or aneurysmal disease. We had hypothesized that degradation of the extracellular matrix scaffold of blood vessels was needed in order to allow for their reshaping, and we pioneered investigations into the role of enzymes called matrix metalloproteinases (MMPs). These can degrade all the extracellular matrix components, as well as can control the biological activity of other molecules involved in tissue remodeling. We demonstrated that MMPs were released by vascular and inflammatory cells in vitro and within the arterial wall under the influence of major drivers of vascular remodeling including hemodynamics, injury, inflammation, and oxidative stress. Using a variety of experimental and clinical observations we also demonstrated that MMP activity was associated with, and indeed was needed, for pathological arterial wall remodeling. Based on these results we proposed that MMPs are major effectors of vascular remodeling in general, and that they can specifically weaken atherosclerotic plaque shoulders (“vulnerable shoulders”). Interest in MMPs and other vascular proteases in relation to physiological and pathological vascular remodeling continues to grow. Accumulated evidence points to potential therapeutic interventions that might prevent or limit the effects of a number of clinical events, such as plaque or arterial wall disruptions. The continued lack of specific synthetic inhibitors restrict the ability to therapeutically control vascular remodeling, suggesting as a potential alternative the manipulation of intrinsic drivers of remodeling, either via risk factors, biological processes, or natural inhibitors, including those that drive and control MMP expression and enzymatic activity.