Endothelial dysfunction in cirrhosis and portal hypertension

Portal hypertension (PHT) is a common clinical syndrome associated with chr onic liver diseases; it is characterized by a pathological increase in port al pressure. Pharmacotherapy for PHT is aimed at reducing both intrahepatic vascular tone and elevated splanchnic blood flow. Due to the altered hemod ynamic profile in PHT, dramatic changes in mechanical forces, both pressure and flow may play a pivotal role in controlling endothelial and vascular s mooth muscle cell signaling, structure, and function in cirrhotics. Nitric oxide, prostacyclin, endothelial-derived contracting factors, and endotheli al-derived hyperpolarizing factor are powerful vasoactive substances releas ed from the endothelium in response to both humoral and mechanical stimuli that can profoundly affect both the function and structure of the underlyin g vascular smooth muscle. This review will examine the contributory role of hormonal- and mechanical force-induced changes in endothelial function and signaling and the consequence of these changes on the structural and funct ional response of the underlying vascular smooth muscle. It will focus on t he pivotal role of hormonal and mechanical force-induced endothelial releas e of vasoactive substances in dictating the reactivity of the underlying va scular smooth muscle, i.e., whether hyporeactive or hyperreactive, and will examine the extent to which these substances may exert a protective and/or detrimental influence on the structure of the underlying vascular smooth m uscle in both a normal hemodynamic environment and following hemodynamic pe rturbations typical of PHT and cirrhosis. Finally, it will discuss the intr acellular processes that regulate the release/expression of these vasoactiv e substances and that control the transformation of this normally protectiv e cell to one that may promote the development of vasculopathy in PHT. (C) 2001 Elsevier Science Inc. All rights reserved.