**3. Vascular smooth muscle**

by diffusion from luminal blood). A schematic of blood vessel anatomy including these three

Lumen

**Figure 1. Blood vessel anatomy.** The three primary circumferential layers of blood vessels include the innermost endo‐ thelium-rich *tunica intima*, the VSM-containing *tunica media*, and the outermost layer the *tunica externa* or adventitia. Elastic laminae exist between these layers as well as within the medial wall. These layers serve critical functions in maintaining normal blood flow and in providing key nutrients and gases to downstream tissues as well as in the re‐ moval of toxic by-products of metabolism. Dysfunction in their physiological abilities, however, can contribute to sig‐

Physiologically, blood vessels hold a critical place in our circulation between the heart, downstream tissues, and the lungs. As such, a major function of blood vessels is to provide blood flow complete with delivery of vital nutrients and gases (oxygen) to these essential tissues and removal of used metabolic by-products and gases (carbon dioxide) targeted for elimination via the lungs. Blood vessels also operate as highways for the distribution of secreted hormones and other endocrine or paracrine factors as well as white blood cells and/or platelets to their sites of action. Blood vessels also aid in the broader distribution of water, solutes, and heat throughout the system. In VSM-specific fashion, blood vessels have ability to regulate luminal caliber and hence, the amount of blood flow they carry, based on local and immediate metabolic needs of downstream tissues. This is of obvious importance for proper vascular function and tissue homeostasis and eutrophy. Blood vessels perform this critical function through abilities to constrict (vasoconstriction) and relax (vasodilation) through mechanisms fully dependent on functional medial VSM. Several other physiological aspects of blood vessels involve their critical roles in growth adaptations during wound healing or following surgical interventions or during vascular adaptations of exercise. These normal blood vessel growth responses can involve angiogenesis (formation of new blood vessels from existing vessels), vasculogenesis (de novo formation of new blood vessels), arborization or branching of existing vessels, and/or collateralization to provide a new blood

nificant vessel disorders including uncontrolled growth which is foundational for the development of CVD.

Adventitia

Media

Intima

critical layers is shown in Figure 1.

6 Muscle Cell and Tissue

supply to an existing vascular bed.

**FIGURE 1**

Elastic laminae As mentioned, the primary structural, muscular, and functional unit of a blood vessel is the medial wall comprised primarily of VSM. In adults, medial wall VSM cells are normally highly differentiated and display a contractile phenotype (with abundant expression of contractile proteins) which enables their abilities to contract and relax. By virtue of vasoconstriction and vasodilation, VSM directly regulates lumen caliber and thus, arterial and venous tone and vascular resistance. These, in turn, control distribution of blood flow in tissue-specific fashion throughout the body. Mechanistically, VSM cells contain many thin actin filaments and relatively few thick myosin filaments, which are arranged along the long axis of these cells. In this arrangement, using the sliding filament theory and numerous states of actin and myosin cross-bridge phosphorylation, VSM utilizes slow force development to produce prolonged force maintenance with low energy utilization, thus helping in the maintenance of tetanic vascular (myogenic) tone and blood flow control. Thus, vasoconstriction and vasodilation represent major physiological functions of contractile VSM.

Under homeostatic unstimulated conditions, adult medial VSM cells are also predominantly quiescent and lack significant growth, "resting" in the nonproliferative G0 phase of the cell cycle. In this differentiated state, VSM cells have low turnover and minimal proliferative or synthetic activities and are dedicated to their primary function of vasoconstriction/dilation. These cells, however, show considerable plasticity and are able to phenotypically switch between quiescent and synthetic phenotypes in response to local stimuli. So, following activation from a variety of agonists, circulating factors, and/or hormones or cytokines or as a result of injury or the onset of disease, these VSM cells dedifferentiate into noncontractile and synthetic cells with reduced expression of contractile proteins and increased capacity to proliferate, migrate, and produce ECM components. During this dedifferentiation process, the cytoskeleton becomes highly organized with defined F-actin filaments, nuclear hypertrophy, and enlarged Golgi. Along with these morphological changes these dedifferentiated cells become highly sensitive to stimulation by mitogenic and chemotactic factors including angiotensin II, platelet-derived growth factor, fibroblast growth factor, interleukins, and tumor necrosis factor alpha. These processes and vasoactive signals allow VSM cells to contribute significantly to the emerging vascular dysfunction through heightened proliferation, migra‐ tion, and synthetic properties foundational to CVD. This conversion to a growth-promoting and synthetic embryonic phenotype represents a key event in the genesis and evolution of numerous cardiovascular pathologies including atherosclerosis, restenosis following bypass grafting or stent deployment, or aneurysmal disease as elements of CVD. Figure 2 shows a schematic of the major functions of a VSM cell under healthy or pathologic conditions.

### **4. Cardiovascular disease**

As discussed, abnormal VSM growth is elemental for development and maintenance of CVD, which has historically ranked as the number one cause of morbidity and mortality in the United **FIGURE 2**

**Figure 2. Vascular smooth muscle cell function.** VSM cells are normally quiescent and operate via vasoconstriction/ vasorelaxation to control local blood flows and pressures and downstream tissue perfusion. However, VSM dysfunc‐ tion leads to dedifferentiation to an embryonic phenotype, and under these pathologic conditions VSM loses its con‐ tractile characteristics and becomes synthetic, proliferative, and migratory, serving as basis for many forms of CVD. Also shown in this schematic are cellular features of thick and thin filaments, dense plaques, and the cytoskeleton.

States and worldwide for many years [1,2]. Despite major advances in our knowledge of the numerous contributing mechanisms for CVD and potential therapeutic strategies against CVD, estimates suggest CVD-related deaths will continue to rise over the next 20 years or so [1,2]. Certainly, notwithstanding these significant basic science and clinical advances, failure in adequate clinical control of CVD highlights its complexity and points to the need for continued study of the underlying mechanisms of and potential routes for control of CVD.

Of the many forms of CVD perhaps the most common is an occlusive disorder termed atherosclerosis. Atherosclerosis is a gradual and progressive disease that involves combined influences of heightened inflammatory status, locally dysfunctional metabolism, abnormal vascular wall growth and remodeling, and the buildup of an occlusive plaque. As discussed, the involvement of uncontrolled VSM growth is a basic foundation of the evolution phase of atherosclerosis, and dedifferentiation of VSM cells into a growth-promoting and synthetic phenotype contributes largely to the emerging and growing plaque. This process of enhanced synthesis and proliferation of medial VSM cells can be slow and progressive and can occur over many decades and may not elicit observable symptoms. This pathology often eventuates in a stenotic plaque, either stable or complicated, which can then become jeopardized and lead to lumen obstruction and diminution of blood flow with clear repercussions of reduced oxygen and nutrient delivery to downstream tissues and diminished removal of toxic metabolites and gases. The plaque can also rupture and send microthrombi into the downstream circulation which can lodge in smaller blood vessels. If atherosclerosis occurs in the peripheral circulation, then these processes could manifest as tissue necrosis with perhaps loss of the affected tissue or limb. Of heightened significance, if this pathology occurs in the cerebral or myocardial circulation, this could result in a cerebral or myocardial infarct (stroke or heart attack) with critical and life-threatening implications.
