Diversity in mechanisms of endothelium-dependent vasodilation in health and disease

Abstract

Small arterioles (40-150 μm) contribute to the majority of vascular resistance within organs and tissues. Under resting conditions, the basal tone of these vessels is determined by a delicate balance between vasodilator and vasoconstrictor influences. Cardiovascular homeostasis and regional tissue perfusion is largely a function of the ability of these small blood vessels to constrict or dilate in response to the changing metabolic demands of specific tissues. The endothelial cell layer of these microvessels is a key modulator of vasodilation through the synthesis and release of vasoactive substances. Beyond their vasomotor properties, these compounds importantly modulate vascular cell proliferation, inflammation, and thrombosis. Thus, the balance between local regulation of vascular tone and vascular pathophysiology can vary depending upon which factors are released from the endothelium. This review will focus on the dynamic nature of the endothelial released dilator factors depending on species, anatomic site, and presence of disease, with a focus on the human coronary microcirculation. Knowledge how endothelial signaling changes with disease may provide insights into the early stages of developing vascular inflammation and atherosclerosis, or related vascular pathologies.

Figure 1

Traditional endothelium-dependent mediators of vasodilation in the microcirculation. Agonists such as bradykinin (BK) and acetylcholine (Ach), or mechanical forces such as shear stress, increase vessel diameter in an endothelium-dependent manner by stimulating production of nitric oxide, or release of arachidonic acid which then is metabolized to prostacyclin or epoxyeicosatrienoic acids. These substances move to the underlying vascular smooth muscle to elicit relaxation through cGMP, cAMP, and/or membrane hyperpolarization, respectively. AA (arachidonic acid); AC (adenylyl cyclase); ATP (adenosine triphosphate); cAMP (cyclic adenosine monophosphate); cGMP (cyclic guanosine monophosphate); COX (cyclooxygenase); CYP450(cytochrome P450 monooxygenase); EDHF (endothelium derived hyperpolarizing factor); EET (epoxyeicosatrienoic acid); GC (guanylyl cyclase); GTP (guanosine triphosphate); Kca (large conductance calcium-activated potassium channel); l-arg (L-arginine); NO (nitric oxide); NOS (nitric oxide synthase); PGI2 (prostacyclin); PLC (phospholipase).

Figure 2

Diversity in endothelium- dependent dilator pathways in the human microcirculation. Depending on the stimulus/agonist applied and the vessel origin, a variety of pathway mediators, including NO, prostanoids, reactive oxygen species, and cytochrome P450 metabolites, contribute to endothelium-dependent dilation. Abbreviations similar to Figure 1. CAD (coronary artery disease); DM (diabetes); H₂O₂ (hydrogen peroxide); HCA (human coronary arterioles); IBD (inflammatory bowel disease); Nl (normal); PG (prostaglandin); PGD2 (prostaglandin D2); SOD (superoxide dismutase).

Figure 3

Schematic depiction of mechanochemical signaling pathway responsible for flow-mediated dilation in human coronary arterioles. Shear stress can activate phospholipases to cleave arachidonic acid from cell membranes. This serves as a substrate for CYP450 monooxygenase production of EETs. These metabolites and/or shear directly activate TPRV4 channels to enhance calcium entry into endothelial cells. The rise in calcium, together with enhanced production of ROS from NADPH oxidase and mechanosensitive factors (unpublished data), stimulates mitochondrial production of superoxide. The mitochondrial-produced superoxide is dismutated to hydrogen peroxide, which diffuses to the vascular smooth muscle cell layer to oxidize cysteine residues of PKG1α, causing homodimerization and activation of the enzyme. The activated dimer opens BK channels on the cell membrane, leading to hyperpolarization and relaxation of the vascular smooth muscle layer. Abbreviations similar to Figure 1. Also: CuZn SOD (copper-zinc superoxide dismutase); MnSOD (Manganese superoxide dismutase); PKG1α (protein kinase G 1α); PLA₂ (phospholipase A₂); TPRV4 (transient receptor potential vannilloid 4).