title: Endothelial cell dysfunction in microvasculature: relevance to disease processes.
abstract: Functional and morphological alterations of microvascular endothelial cells (ECs) would lead to microcirculatory disturbances, thereby providing a basis for the development of a disease state. Clinically endotoxemia frequently encountered in a variety of diseases is considered to be a trigger to develop the microcirculatory disorders such as disseminated intravascular coagulation (DIC) and multiple organ failure (MOF), both of which feature the end stage of severe systemic disease. Experimentally intravital microscopy reveals that continuous venous infusion of endotoxin (LPS) causes a low flow state in the rat mesenteric microcirculatory unit. By vital stain with monastral blue B (MBB), the microvascular ECs are focally positive for MBB at the postcapillary venular site, where leukocytes adhere and extravasate. As shown in the histamine-induced diapedesis by transmission electron microscopy, the MBB-positve venular ECs may correspond to the contracted ECs, enabling the polymorphonuclear leukocytes and erythrocytes to extravasate through the widened gaps between the contracted ECs. Actin filaments proven in the microvascular ECs by electron microscopy may play a modulating role in this neutrophil diapedesis. In the process of gastric ulcer formation under restrained stress to the rat, the ECs of microvessels in the gastric mucosa, particularly of the mucosal capillaries and postcapillary venules directly innervated by the cholinergic nerves, are altered by the stress-induced overstimulation of the autonomic nerves, inducing the diapedesis of leukocytes and erythrocytes followed by hemorrhagic and ischemic injuries in the gastric mucosa. Liver cirrhosis also accompanies endotoxemia. The most prominent electron microscopic alterations of hepatic microvasculature are a decrease of hepatic sinusoidal endothelial fenestrae (SEF) both in diameter and in number, and the formation of basement membranes beneath the hepatic sinusoidal ECs. These ultrastructural changes would be induced by a most potent vasoconstrictor endothelin (ET)-1 through the overexpressed ET(A) and ET(B) receptors on the hepatic stellate cells and the sinusoidal ECs, contributing to the development of portal hypertension as well as to the disturbance in excretion of endotoxin into the bile canaliculi via the hepatocytes from the circulating sinusoidal blood to prevent endotoxemia.
authors.affiliation: Department of Internal Medicine, School of Medicine, Keio University, Tokyo, Japan. m-oda@med.keio.ac.jp
authors.forename: M
authors.initials: M
authors.lastname: Oda
authors.forename: J Y
authors.initials: JY
authors.lastname: Han
authors.forename: M
authors.initials: M
authors.lastname: Nakamura
mesh_terms: D008841:Actin Cytoskeleton / Q000502:physiology; D000662:Amphetamines; D000818:Animals; D001692:Biological Transport; D002196:Capillaries / Q000378:metabolism / Q000648:ultrastructure; D019559:Capillary Leak Syndrome / Q000503:physiopathology; D002634:Chemotaxis, Leukocyte / Q000187:drug effects; D002799:Cholinergic Fibers / Q000502:physiology; D004396:Coloring Agents / Q000493:pharmacokinetics; D016232:Endothelins / Q000502:physiology; D004730:Endothelium, Vascular / Q000166:cytology / Q000502:physiology* / Q000503:physiopathology; D006632:Histamine / Q000494:pharmacology; D006801:Humans; D006975:Hypertension, Portal / Q000209:etiology / Q000503:physiopathology; D007103:Immobilization / Q000009:adverse effects; D007211:Indoles / Q000493:pharmacokinetics; D008102:Liver Circulation; D008103:Liver Cirrhosis / Q000150:complications; D008833:Microcirculation / Q000502:physiology*; D008954:Models, Biological; D009569:Nitric Oxide / Q000502:physiology; D009942:Organometallic Compounds / Q000493:pharmacokinetics; D010437:Peptic Ulcer / Q000209:etiology / Q000503:physiopathology; D051381:Rats; D017466:Receptors, Endothelin / Q000187:drug effects / Q000502:physiology; D013152:Splanchnic Circulation / Q000187:drug effects; D013270:Stomach / Q000098:blood supply / Q000294:innervation; D013312:Stress, Physiological / Q000150:complications
chemical_list: D000662:Amphetamines; D004396:Coloring Agents; D016232:Endothelins; D007211:Indoles; D009942:Organometallic Compounds; D017466:Receptors, Endothelin; C100229:amphetaminil; D009569:Nitric Oxide; C015445:copper phthalocyanine; D006632:Histamine