**2. Overview of vascular anatomy and physiology**

**1. Introduction**

4 Muscle Cell and Tissue

against CVD.

Our circulatory system is comprised of a vast network of cellular elements and organs that includes the heart, lungs, and vasculature composed of arteries, veins, and lymphatics. These integrated factors serve essential roles in controlling flow of blood and lymph and in the transport and delivery of essential nutrients, nutritive and vasoactive factors, and hormones and gases. Vascular smooth muscle (VSM), the primary functional constituent of blood vessels, serves critical regulatory roles of vessel relaxation and contraction to ensure adequate tissue blood flow and to maintain proper localized arterial blood pressures and perfusion of downstream tissues. These processes are elemental for normal vascular eutrophy and homeo‐ stasis and overall body health. Abnormalities in VSM anatomy and physiology, however, can contribute to a myriad of primary and secondary vessel pathologies. Moreover, adult blood vessels are normally contractile, quiescent, and static. However, under inimical conditions like those associated with cardiovascular disease (CVD), VSM cells undergo phenotypic alterations and revert to a growth-promoting, synthetic nature. In turn, this abnormal growth significantly contributes to the emerging cardiovascular disorder. These complications alone present significant health risks but also serve as confounding risk factors for associated cardiovascular complications including hypertension, hypercholesterolemia, diabetes, and metabolic syn‐ drome. In fact, recent statements by the American Heart Association [1] and the World Health Organization [2] point to dysfunctional VSM as a primary underpinning behind CVD. Logically, therapeutically targeting VSM for clinical interventions aimed at controlling and

The term "cardiovascular disease" defines a wide range of disorders, diseases, and conditions that deleteriously affect the heart and blood vessels. If the heart is the primary organ affected then this can include heart failure, various myopathies, arrhythmias and/or conduction delays, valve complications, myocarditis and/or pericarditis. If the disorder is vascular in origin, then problems could consist of occlusive plaque formation and atherosclerosis, arteriosclerosis, coronary and/or peripheral artery disease (PAD), aneurysm formation, and/or restenosis and remodeling. There are numerous forms and manifestations of CVD as well as broad prognoses based on form and severity of the disorder. Abnormal biology of the vessel wall constitutes a major element in the pathogenesis of most forms of CVD [1], and therefore the vessel wall and particularly VSM makes a prime target for further discovery and potential therapeutic utility

The overall goal of this chapter is to present some of the more recent and novel theories surrounding the primary vessel wall constituent, VSM, its importance in CVD, and its promise as a therapeutic target. Discussion will include succinct overviews of normal vascular elements and physiology with a focus on VSM, some common forms of CVD and their pathologies, the role of VSM dysfunction in CVD etiology, the influence of flow alterations and hemodynamic forces in vessel physiology and pathology, neural control of VSM and the vascular network, unique molecular and cellular signaling pathways that may offer innovative and precise targets for therapy in VSM, current therapeutic paradigms, and treatment strategies used to combat VSM pathobiology ranging from homeopathic lifestyle modifications to pharmaco‐

hopefully eradicating CVD is highly significant and essential.

Upon leaving the heart, blood enters the vasculature which is comprised of diverse tissues and cell types. Conduit, large and small arteries, arterioles, capillaries, venules, veins, and lym‐ phatics are basic elements of this system, each with unique characteristics and functions. The composition of the walls of each of these vessels also differs, based on size, location, and function, and this dictates the presence or absence of the three major vessel wall layers. Starting from the lumen that carries blood, the innermost blood vessel wall layer is the *tunica* (Latin for tunic, membrane, coat) *intima*, and this is formed by squamous vascular endothelial cells (VECs), a layer of connective tissue termed internal elastic lamina, and a basement membrane containing laminin, heparan sulphate proteoglycans and collagen, and often the glycosami‐ noglycan hyaluronan. The *tunica intima* provides a key, selectively permeable interface between flowing blood (which contains abundant growth factors and thrombogenic platelets) in the lumen and the highly thrombogenic components of the subintimal vessel wall. This important intimal layer is also largely responsible for controlling inflammation and medial VSM proliferation and migration, and these intimal VECs operate by eliciting crucial signals that, in communication with underlying VSM, help control blood vessel function. Hence, this layer is of utmost importance in maintaining normal vascular homeostasis. Interestingly, the endothelium of the *tunica intima* is continuous with the endocardium of the heart and is the only layer present in all blood vessels of all sizes and anatomical locations.

The thick and muscular middle layer of blood vessels is called *tunica media* and this is composed mainly of helical, spindle-shaped mononuclear VSM cells. The media also contains sparse macrophages and fibroblasts along with an interstitial matrix consisting of collagens; glyco‐ proteins such as tenascin, vitronectin, and fibronectin; chondroitin sulphate proteoglycans including versican; and elastic laminae. The *tunica media* provides structural support to blood vessels and is the primary functional element that controls vascular constriction and dilation (and hence, blood flow) based on metabolic needs of the downstream tissues. VSM within the *tunica media* (in communication with intimal VECs) is predominantly responsible for mainte‐ nance of normal vascular physiology, yet dysfunction of medial VSM cells (and VECs) is a major contributor to the pathogenesis of CVD (discussed later). The outermost layer of blood vessels is termed *tunica externa* or adventitia, which is separated from the medial wall by the external elastic lamina and is made up of sparse VSM and nerve cells, fibroblasts, fat cells, and abundant connective tissue including elastin, collagen, and glycosaminoglycans that provide structural support as the extracellular matrix (ECM). In larger caliber vessels, the adventitia also contains unique small blood vessels termed *vasa vasorum* that feed nutrients to the thick muscular vessel wall (when the vessel wall cannot get adequate oxygen and nutrition simply **FIGURE 1**

by diffusion from luminal blood). A schematic of blood vessel anatomy including these three critical layers is shown in Figure 1.

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

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 supply to an existing vascular bed.
