The Aging Risk and Atherosclerosis: A Fresh Look at Arterial Homeostasis

Abstract

A considerable volume of research over the last decade has focused on understanding the fundamental mechanisms for the progression of atherosclerosis-the underlying cause for the vast majority of all cardiovascular (CVD)-related complications. Aging is the dominant risk factor for clinically significant atherosclerotic lesion formation, yet the heightened impact of aging on the disease is not accounted for by changes in traditional risk factors, such as lack of physical activity, smoking, hypertension, hyperlipidemia, or diabetes mellitus. This review will examine the pathological and biochemical processes of atherosclerotic plaque formation and growth, with particular focus on the aging risk vis-a-vis arterial homeostasis. Particular focus will be placed on the impact of a number of important contributors to arterial homeostasis including bone marrow (BM)-derived vascular progenitor cells, differential monocyte subpopulations, and the role of cellular senescence. Finally, this review will explore many critical observations in the way the disease process has been reassessed both by clinicians and researchers, and will highlight recent advances in this field that have provided a greater understanding of this aging-driven disease.

Keywords: aging; arterial homeostasis; atherosclerosis; bone marrow-derived vascular progenitor cells; cardiovascular disease; risk factors; vascular repair.

Figure 1

Hemodynamic forces exerted on the arteries. (A) Trans-mural pressure exerted radially across the vessel wall. (B) Endothelial Shear Stress (ESS), determined as the product of blood viscosity (η) and its shear rate (^δv/_δy) such that ESS = η • (^δv/_δy). (C) Typical sites of atherosclerotic plaque formation (lateral walls of bifurcations, inner wall of vessel curvature, and near branch points). Laminar flow in these regions is disrupted, causing oscillatory or reversed flow and subsequent low ESS. Comparison of the ability of bone marrow (BM)-derived vascular progenitor cells and other reparative factors to interact with injured endothelial cells under (D) laminar or (E) turbulent flow can be envisioned as the difference between landing a plane under calm or stormy conditions, respectively.

Figure 2

Formation and progression of an atherosclerotic plaque. As an inflammatory disease, the initial stages of atherosclerosis involve an inflammatory insult to the endothelial cells lining the artery lumen. Bone marrow (BM)-derived progenitor cells have been shown to be critical in responding to vascular injury, effecting vascular repair and maintaining homeostasis. In the absence of vascular repair, injured endothelial cells begin to express adhesion molecules that facilitate the transmigration of monocytes into the vessel intima. These monocytes then differentiate into macrophages and begin engulfing lipid and lipid products, forming foam cells. As foam cells aggregate, they form the characteristic fatty streak, while many macrophages begin to undergo apoptosis. Inefficient clearance of apoptotic macrophages leads to secondary necrosis, resulting in a growing lipid-rich necrotic core. In response to the growing lesion, smooth muscle cells migrate to the intima, helping to form the overlying fibrous cap. Rupture of this cap can expose the necrotic core, leading to thrombus formation and subsequent acute cardiovascular events.

Figure 3

A visualization of alternative fates of vascular inflammation. In the presence of healthy BM-derived vascular progenitor cells capable of arterial repair, inflammation subsides and vanishes (negative feedback loop), resulting in the maintenance of vascular homeostasis. In the absence of sufficient BM-derived vascular progenitor cells, or if such cells are no longer capable of arterial repair, inflammation continues or even expands, resulting in potential dysfunctional remodeling, continued cell senescence, and propagation of arterial injury (positive feedback loop). However, successful treatments have been established such as statin therapy, which has been shown to reduce circulating LDL-Cholesterol (LDL-C), increase HDL-Cholesterol (HDL-C), reducing inflammation and dysfunctional remodeling (Nozue et al., 2013); Human Allogeneic Mesenchymal Stem Cells (HAMSC) (Tompkins et al., 2017), and possibly other progenitor cells (Song et al., 2012), may be able to reverse arterial tissue senescence and improve arterial repair without affecting circulating lipids; and anti-inflammatory molecules such as Canakinumab have also been shown to reduce destructive inflammation without affecting circulating lipids (Ridker et al., 2017). Hence, our armamentarium to prevent, stabilize or even reverse atherosclerosis and its thromboembolic complications are becoming increasingly effective at promoting arterial homeostasis.