Atherogenesis and Vascular Biology

Atherogenesis. Introduction. Atherosclerotic disease is highly prevalent throughout the world and is the principal cause of morbidity and mortality in Western nations for both men and women. Atherosclerosis is pathophysiologically complex and begins at an early age (fatty streaks can be found in children and adolescents), with anatomically apparent coronary disease frequently becoming apparent in the third decade of life though it tends to remain clinically silent until the sixth or seventh decade.

Atherogenesis is driven by highly evolved networks of histologic, rheologic, autoimmune, oxidative, inflammatory, and thrombotic responses to vascular injury. These networks engage in extensive cross talk. Once established, the rate of disease progression is influenced by numerous risk factors, including age, multiple forms of dyslipidemia, hypertension, sympathetic tone, cigarette smoking, obesity, sedentary lifestyle, chronic kidney disease, the intensity of underlying inflammation, depression, insulin resistance, diabetes mellitus, urbanization, air pollution, and perhaps some forms of infection.

In the past six decades, an enormous range of scientific, epidemiologic, and clinical research has shown that the control of modifiable risk factors through lifestyle adjustments and pharmacologic therapies slows or even reverses the trajectory of atherosclerosis. Statin treatment is known to improve endothelial function, reduce inflammation, stabilize established atherosclerotic plaque, and reduce risk for such complications as myocardial infarction (MI), transient ischemic attack and stroke, claudication and peripheral arterial disease, cardiovascular and all-cause mortality, and the need for revascularization via angioplasty/stenting or bypass grafting.

Early identification and treatment of risk factors are tantamount to the long-term prevention of atherosclerotic disease given the fact that the number of risk factors, their severity, and the duration of exposure determine lifetime risk. Consequently, evaluating global cardiovascular risk burden, quantifying 10-year or lifetime risk, and treating each identified risk factor (e.g., dyslipidemia, hypertension, diabetes mellitus) to current guideline targets are of the essence before the onset of such clinical signs and symptoms as angina pectoris or claudication.

Unfortunately, little progress has been made in primordial prevention as guideline writing bodies are hesitant to make recommendations for treating adolescents and young adults. In a very real way, we typically wait until patients develop coronary or peripheral vascular disease before risk factors are identified and treated. Risk factor goal attainment rates even in patients with advanced, unstable disease tend to be distressingly low. There continues to be considerable clinical inertia in the treatment of risk factors. Undertreatment of risk factors does not constitute appropriate or adequate treatment of risk factors, especially if the therapeutic goal is the prevention of disease.

The arterial system is not a simple tubular conduit network. Arteries are histologically and biochemically complex, dynamic structures that are highly responsive to their milieu. They are endowed with a wide variety of receptors along the endothelium and smooth muscle cells that regulate vasomotor tone (i.e., the capacity to regulate vasoconstriction and vasorelaxation as demanded by physiological circumstances).

The coronary and cerebral vasculature are tightly regulated and fine-tuned to the oxygen delivery needs of the myocardium and the brain via local pressor effects (nitric oxide, prostacyclin, endothelin-1) as well as sympathetic and parasympathetic inputs. The coronary and peripheral vasculature (cerebrovasculature and lower extremity arteries) are continually exposed to multiple atherogenic stimuli that act additively to potentiate the pathophysiology underlying atherogenesis in the majority of persons. Atherosclerosis is a diffuse disease that, when left untreated, tends to progress throughout life.

Arterial Structure. Arteries are highly evolved, responsive conduit vessels for blood and, one of its most important constituents, oxygen. Oxygen must be available to aerobic cells in order to function as a terminal electron acceptor for mitochondrial oxidative phosphorylation. During embryological vasculo- genesis, the arterial wall differentiates into three layers with distinct cellular and connective tissue constituents: these are the intima, media, and adventitia. The intima is composed of (1) an endothelial cell monolayer that interfaces with blood and (2) the lamina propria which contains smooth muscle cells, fibroblasts, collagen, and intercellular matrix that comprised glycosaminoglycans (hyaluronate, heparin/heparan sulfate).

The media is composed of smooth muscle cells which regulate arterial tone and blood pressure by either contracting or relaxing in response to a variety of vasoactive molecules (e.g., nitric oxide, catecholamines, prostacyclin, bradykinin, endothelin-1, angiotensin II). The media is separated from the intima and adventitia by the internal and external elastic membranes, respectively. During athero- genesis, smooth muscle cells in the media can undergo activation via platelet-derived growth factor or cell surface lipoprotein binding proteins, rearrange their actin cytoskeleton, extend pseudopodia, and migrate into the intima where they are incorporated into atheromatous plaques.

The smooth muscle cell is able to migrate by releasing proteases into its surroundings which hydrolyze the intercellular matrix and the internal elastic membrane. The adventitia contains fibroblasts, elastin, and collagen. The vasa vasora and sympathetic and parasympathetic nerve fibers are contained in the adventitia. The arterial wall is a highly dynamic and responsive environment with the various cellular constituents of different layers communicating through complex signaling circuits. Arteries undergo a staggering series of changes, both biochemically and physiologically, during all stages of atherogenesis.