Vascular Physiology

Intrinsic and Extrinsic Vasomotor Control

Vasomotor tone is influenced by the intrinsic properties of the vessel wall, by local innervation, and by substances from surrounding parenchymal tissue. This regulation of vasomotor tone is critically involved in organ perfusion. Vascular responses to endogenous substances are summarized in Figure 48-4 . All these factors have an especially significant role in the setting of microvascular tone.

Based on in vitro observations, Jones and colleagues found that larger arterioles are more sensitive to shear stress than myogenic factors, whereas small microvessels are more sensitive to metabolic factors. They organized arterial microvessels into three microdomains as governed by distinct forms of regulation based on vessel size: (1) small arterioles (<50 µm), most sensitive to metabolic mediators; (2) intermediate arterioles (50 to 80 µm), most sensitive to myogenic mechanisms; and (3) large arterioles (80 to 150 µm), most sensitive to flow-induced dilation. Undoubtedly, there is overlap among these three components; however, this model provides a framework for understanding the regulation of microvessels.

Jones and colleagues hypothesized that the longitudinal disposition of these three microdomains enables integrated adjustment of flow conductance in the face of various influences, such as increased metabolism or a reduction in perfusion pressure. For example, dilation of small arterioles by augmented metabolism produces a decrease in luminal pressure in upstream microvessels, leading to the dilation of intermediate arterioles by decreasing the myogenic tone. These microvascular dilations could also produce an increase in shear stress and result in enhanced flow-induced dilation in large arterioles. As a result, all sizes, or domains, of arterial microvessels dilate in response to the metabolic stimulation. The marked longitudinal heterogeneity of microvascular responses may be at least partly explained by this microdomain hypothesis.

Role of the Endothelium

The endothelium plays a pivotal role in vasomotor tone regulation. Many substances affect tone via endothelium-mediated mechanisms. Endothelial cells also release several substances that affect coronary resistance, including vasodilators such as nitric oxide (NO•), prostaglandins, and vasoconstrictors including angiotensin converting enzyme endothelin, and reactive oxygen species (summarized in Fig. 48-5 ). As the major regulatory molecule, NO• is produced by a constitutively expressed enzyme known as endothelial nitric oxide synthase (eNOS or NOS-3). NO• is formed as a result of a series of electron transfers from reduced nicotinamide adenine dinucleotide phosphate (i.e., NADPH) to flavin adenine dinucleotide (FAD) and flavin mononucleotide (FMN) on the reductase domain, and electron transfer to a prosthetic heme group in the oxygenase domain. When heme reduction occurs, arginine is catalyzed to citrulline and NO•. The NO• formed diffuses to underlying vascular smooth muscle, where its actions include stimulation of soluble guanylate cyclase, increasing the level of cyclic guanosine monophosphate (cGMP) and prompting vasodilation via activation of cGMP-dependent protein kinase. Although binding of calcium and calmodulin is a prerequisite for activity of eNOS, other events, such as phosphorylation, membrane binding, binding of eNOS with heat-shock protein 90, and association with the integral membrane protein caveolin can also modulate NOS activity. In addition, NO• can undergo reactions with thiol-containing compounds to form biologically active nitroso molecules.

Although eNOS is expressed constitutively, it undergoes important gene expression regulation by factors such as shear stress, endothelial cell growth, hypoxia, exposure to oxidized low-density lipoprotein, and exposure to cytokines. In the coronary circulation, the release of NO• confers a state of basal vasodilation; therefore, administration of NO• synthase antagonists increases resting coronary resistance. However, when substances such as acetylcholine and bradykinin are administered, coronary microvessels of all sizes dilate, resulting in decreased coronary resistance. Endothelial NO• production is affected by a variety of mechanisms in many disease states. The signal transduction pathways through which NO• acts are summarized in Figure 48-6 . It is likely that the most important pathway involves activation of soluble guanylate cyclase, which catalyzes the formation of cGMP from guanidine triphosphate. The cGMP serves as an allosteric regulator of the enzyme cGMP-dependent protein kinase, which phosphorylates contractile proteins and ion channels, decreasing intracellular calcium and the sensitivity of contractile proteins to intracellular calcium. The binding of NO• to cytochrome oxidase in the mitochondria alters oxygen consumption and in turn can affect oxygen demand. Similarly, receptors for atrial natriuretic peptide and brain natriuretic peptide are also the particulate forms of guanylate cyclases, and these signal vasodilation via similar pathways. NO• is also released in response to sodium nitroprusside and organic nitrates.

Although NO• is the major regulator of vascular tone, there are other factors that modulate endothelium-dependent vascular tone in coronary, pulmonary, and peripheral circulations. Endothelium-derived hyperpolarizing factor (EDHF) is an example. The endothelium-dependent hyperpolarization of vascular smooth muscle is mediated by the opening of a calcium-dependent potassium channel, leading to K+ exit from the cell. When the vascular smooth muscle is hyperpolarized, voltage-sensitive calcium channels are closed, leading to a reduction in intracellular calcium. The role of the various EDHFs probably varies depending on the vessel size, the species, and the vascular bed under consideration. It is likely that several EDHFs exist, but current evidence suggests that hydrogen peroxide and epoxyeicosatrienoic acid, a cytochrome p450 metabolite of arachidonic acid, play major roles. Hydrogen peroxide is formed by the mitochondria in response to shear stress and acetylcholine. The hydrogen peroxide not only opens large conductance potassium channels; it also activates protein kinase G, causing oxidation and dimerization. Prostaglandin synthesis by the endothelium also modulates tone in the microcirculation. The predominant prostaglandin produced by endothelial cells is prostacyclin. There is substantial interaction between NO•, EDHF, and prostacyclin. A major stimulus for release of these factors is shear stress, or the tangential force of fluid as it flows over the endothelium, resulting in flow-dependent vasodilation. Interestingly, the importance of NO• seems to decline and the role of the EDHF increases as blood vessels decrease in size. In addition, the production of EDHF may increase when NO• is low. The interaction of endothelial cells with vascular smooth muscle cells and the intermediates involved is outlined in Figure 48-7 .

Role of Metabolism and Autoregulation

The ability of a vascular bed to adjust its tone to maintain a constant flow during changes in perfusion pressure is termed autoregulation. This process is most effective in the coronary circulation when pressure is between 40 and 160 mm Hg. The subendocardium and subepicardium differ in the range of pressures over which autoregulation can be observed. In the subendocardium flow begins to decrease at pressures of less than 60 to 70 mm Hg, whereas in the subepicardium these decreases in flow occur at significantly lower pressures. Clinically, systemic arterial hypertension affects the range over which autoregulation occurs in the subendocardium, such that flow begins to decline at even higher pressures. Such a change in subendocardial perfusion pressure in the setting of hypertrophic myocardium increases the likelihood of subendocardial ischemia. Patients with systemic hypertension may have an increased lower limit of autoregulation and may be more likely to suffer brain ischemia during surgery, or other times, even at pressures sufficient to sustain adequate perfusion in patients with normal blood pressure.

The predominant changes in vasomotor tone, concerning both autoregulation and metabolic vascular regulation, occur in vessels smaller than 100 µm in diameter. The rate of oxygen consumption in the myocardium is closely related to myocardial perfusion via coronary microvascular tone. The ability of the myocardium to extract additional oxygen to meet increased demand is limited because myocardial oxygen extraction is already near its maximal threshold under resting conditions. To account for this limitation, coronary flow rises in response to increased myocardial oxygen requirements.