Vascular biology and pathobiology of the liver: Report of a single-topic symposium

Abstract

Portal hypertension and its complications account for the majority of morbidity and mortality that occurs in patients with cirrhosis. In addition to portal hypertension, a number of other vascular syndromes are also of great importance, especially the ischemia-reperfusion (IR) injury. With the identification of major vascular defects that could account for many of the clinical sequelae of these syndromes, the liver vasculature field has now integrated very closely with the broader vascular biology discipline. In that spirit, the Vascular Cell Signaling Mediated by NO. Endothelial cells (ECs) produce NO through the enzyme endothelial NO synthase (eNOS). NO then regulates important vascular functions, such as vascular tone, angiogenesis, and arterial remodeling. 1 eNOS is regulated in a multiprotein complex (Fig. 1), which includes the activating kinase, Akt1 and putative negative regulator caveolin-1 (Cav-1). Although eNOS Ϫ/Ϫ mice evidence impaired angiogenesis, overexpression of a constitutively active allele of eNOS that mimics the phosphorylated and active state rescues these angiogenic defects. 2 Because eNOS is an EC-specific Akt substrate, ECs from mice lacking the Akt1 isoform also have defects in eNOS phosphorylation, NO production, and angiogenesis which are correspondingly rescued by Akt1 overexpression. 3 One key mechanism by which the Akt-eNOS axis promotes angiogenesis in vivo is through mobilization of endothelial progenitor cells and EC migration to sites of vascular injury. In contradistinction to AKT, Cav-1 is a negative regulator of eNOS. Mice deficient in Cav-1 have defective mechanotransduction, calcium signaling, prostacyclin production, and elevated NO production indicating that endothelial Cav-1 also importantly regulates vascular function by regulating eNOS and other signaling pathways. 4 Upon its generation in ECs, NO also acts on adjacent vascular effector cells to modulate vascular tone, cellular proliferation, apoptosis, migration, and synthesis of extracellular matrix (Fig. 2). NO acts in part by stimulating soluble guanylate cyclase (sGC) to produce intracellular Abbreviations: Cav-

Hepatic sinusoids in liver injury, inflammation, and fibrosis: new pathophysiological insights

“…In liver disease, the SEC phenotype changes dramatically [1,14]. Liver injury leads to endothelial dysfunction with loss of fenestrae and deposition of a basement membrane, a process that is known as capillarization [6,15,16].…”

Hemodynamics and pharmacokinetics of tezosentan, a dual endothelin receptor antagonist, in patients with cirrhosis

“…In patients with cirrhosis, portal hypertension develops as a consequence of both hyperdynamic circulation and increased hepatic vascular resistance mediated by several neurohormones, including endothelins [1,2]. Endothelin is one of the most potent and long-lasting vasoconstrictors isolated [3].…”

Aquaporin-1 Promotes Angiogenesis, Fibrosis, and Portal Hypertension Through Mechanisms Dependent on Osmotically Sensitive MicroRNAs

“…1 In concert with this progressive fibrogenesis, pathological changes in the hepatic angioarchitecture also occur and are thought to promote fibrosis, portal hypertension, and their clinical sequelae. [2][3][4] Despite intensive investigations and significant insights into the basic mechanisms driving these processes, no effective anti-fibrotic therapies are yet available for use in patients with chronic liver diseases. Thus, further mechanistic insights into liver fibrogenesis and coinciding events, such as pathological angiogenesis, are needed to identify potential anti-fibrotic targets and translate those into advances in clinical care.…”