Applying the Input Output Analogy to Cardiac Microvasculature in Health

The notion that the endothelium represents a series of input-output devices is helpful when considering the vascu-lature or endothelium during development and in the postnatal period. A consideration of cardiac development is beyond the scope of this chapter. The following section will focus on the adult cardiac endothelium.

Conduit and Resistance Vessels

The endothelium of the coronary and resistance vessels has presumably evolved to optimize the transport blood (oxygen and nutrients) to the myocardium. Compared with capillaries or veins, the arterial/arteriolar endothelium is exposed to higher oxygen concentration and shear stress. Like other segments of the cardiac vasculature, the arterial endothelium also experiences forces generated by contraction of the heart. On the abluminal side the endothelium receives signals from extracellular matrix and vascular smooth muscle cells. Based on studies of the heart and other organs, the arterial endothelium differs from its capillary and venous counterparts in morphology, gene and protein expression profiles, and cellular function. As one example, endothelial cells lining the resistance vessels express the highest amounts of endothelial nitric oxide syn-thase (eNOS), a pattern that is consistent with the established role of nitric oxide (NO) in regulating coronary vascular tone.

The tight coupling of myocardial oxygen consumption and coronary flow may be attributed, in part, to cross talk between cardiomyocytes and resistance vessels. Indeed, it has been proposed that coronary blood flow involves a dynamic, metabolically regulated balance in the production of cardiomyocyte-derived vasodilators (e.g., adenosine, NO, prostacyclin, and bradykinin) and vasoconstricting molecules (e.g., angiotensin II). Whether these and/or other car-diomyocyte-derived factors directly engage vascular smooth muscle cells or communicate indirectly via the endothelium is not known.

Capillaries

Whereas the endothelial lining of arteries and arterioles has evolved to optimize conduit function, the capillary endothelium is adapted to meet the unique and high meta bolic needs of the myocardium. If one considers the arteries and arterioles as analogous to train tracks, the capillaries represent the train station—the site where circulating molecules and cells leave and enter the blood. As an input-output device, the endothelium senses numerous mechanical forces, including pressure generated during the cardiac cycle. With each heart contraction, the pressure may result in reduced diameter and flow, particularly in the intramural and subendocardial vessels. The capillary endothelial cell is exposed to multiple biochemical stimuli arising from the blood and abluminal surface (Figure 2). The cardiomyocyte secretes many factors that potentially act in paracrine pathways to maintain or modulate endothelial cell phenotype, including vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), and platelet-derived growth factor (PDGF). VEGF may play a role not only in new blood vessel formation, but also in maintaining survival and adaptive function of the endothelium. On the output side, capillary endothelial cells express a unique pattern of genes and proteins. Moreover, these cells secrete myriad factors that interact with underlying cardiomyocytes, thus contributing to a bidirectional communication between the two cell types. For example, endothelial cells in the myocardium produce NO, endothelin, angiotensin, and prostacyclin, each of which may influence cardiac metabolism and growth, contractile function and conduction. At a functional level, the endothelium participates in the local balance of hemostasis, leukocyte trafficking, and survival/apoptosis. Endothelial cells (together with pericytes) play a critical role in mediating new blood vessel formation. Angiogenesis depends on the sprouting of preexisting capillaries or postcapillary venules, whereas collateral growth (variably termed arteriogenesis) arises from an outward remodeling of preexisting arterioles or small arteries. Angiogenesis normally results in blood vessels of capillary diameter (5 to 8 mm), while arteriogenesis gives rise initially to 10 to 20 mm resistance arterioles and ultimately to conductance arteries. The formation or remodeling of blood vessels depends on the concerted activity of soluble factors released by cardiomyocytes (e.g., VEGF and bFGF), endothelium (e.g., NO), and monocytes (e.g., urokinase-type plasminogen activator, metalloproteinases). Interestingly, there is increasing evidence for the role of endothelial progenitor cells in postnatal blood vessel formation (vasculogenesis) in the setting of cardiac ischemia. The elucidation of the molecular control of angiogenesis, arteri-ogenesis, and vasculogenesis represents an important foundation for novel cardiovascular therapies.

Flgure 2 Schematic of cardiac endothelium in health. The endothelium of the artery and arteriole is exposed to comparatively high shear stress and communicates with neighboring smooth muscle cells in the blood vessel wall. In addition to maintaining blood fluidity and barrier function, the endothelial lining of the arteries and arterioles contributes to the control of vasomotor tone. The cross-sectional area of the capillaries is far greater than that of the arteries and veins, thus reducing shear stress at the level of the endothelium and facilitating exchange of oxygen and nutrients with underlying tissue. Multiple input signals arise from the luminal surface (shown is blood flow) and abluminal surface (shown is communication with pericytes and cardiomyocyte, extracellular matrix [ECM], and contractile force). The capillary endothelium plays a critical role in maintaining the viability and function of the myocardium. The endothelium lining the postcapillary venules is the primary site for leukocyte trafficking. (see color insert)

Flgure 2 Schematic of cardiac endothelium in health. The endothelium of the artery and arteriole is exposed to comparatively high shear stress and communicates with neighboring smooth muscle cells in the blood vessel wall. In addition to maintaining blood fluidity and barrier function, the endothelial lining of the arteries and arterioles contributes to the control of vasomotor tone. The cross-sectional area of the capillaries is far greater than that of the arteries and veins, thus reducing shear stress at the level of the endothelium and facilitating exchange of oxygen and nutrients with underlying tissue. Multiple input signals arise from the luminal surface (shown is blood flow) and abluminal surface (shown is communication with pericytes and cardiomyocyte, extracellular matrix [ECM], and contractile force). The capillary endothelium plays a critical role in maintaining the viability and function of the myocardium. The endothelium lining the postcapillary venules is the primary site for leukocyte trafficking. (see color insert)

Endothelial cells from the capillaries of the heart (as well as those in the arteries, arterioles, venules, and veins) may possess a distinct "set point," defined as epigenetically programmed switches in phenotype. According to this hypothesis, certain properties of the capillary cells are irreversibly "locked in" by site-specific environmental factors—either during development or in the postnatal period. Although there is compelling evidence that endothelial cells from the epicardial arteries and the endocardium are derived from different subpopulations of precursor cells, little is known about the embryonic origin of capillary endothelial cells. The observation that capillary endothelial cells undergo phenotypic drift in tissue culture, and that this effect is partially reversed by coculture with cardiomyocytes, suggests that at least certain vascular bed-specific properties of these cells are reversibly regulated by the microenvironment. It is important to note that the retention of certain vascular bed-specific properties in vitro does not provide evidence for "genetic predetermination"—after all, each and every cell in the human body has an identical genome. Rather, such findings point to the influence of an epigenetic process at some point during the life of that cell. The distinction between endothelial cell phenotypes dependent on signal input and those that are governed by set point has important therapeutic implications. For example, diabetes is associated with phenotypic changes in microvascular endothelium. Are these changes reversible with correction of the metabolic disease? Or are certain phenotypes irreversibly and indelibly imprinted on the endothelium through modification of the genome? If the latter is correct, then the reversal of endothe-lial cell "dysfunction" associated with diabetes will be considerably more challenging.

As a result of differences in input signal and set point, the properties of the endothelium differ between different segments of the vasculature within the heart, and even between neighboring endothelial cells within the same vessel. For example, von Willebrand factor (vWF) is expressed at higher levels within the veins of the heart, compared with the arteries or capillaries. eNOS expression is highest in the endocardial and coronary artery endothelium. As a final example, the receptor-type protein tyrosine phosphatase m is expressed predominantly on the arterial side of the cardiac vasculature.

Venules

Venules and veins function as conduit vessels to deliver deoxygenated blood to the right atrium. Postcapillary venules are the primary site for leukocyte-endothelial interactions and transmigration of leukocytes into the suben-dothelial space. The propensity for trafficking to occur in postcapillary venules may be explained by the low flow state and/or differential expression of cell adhesion molecules.

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Essentials of Human Physiology

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