Regulation of Sinusoidal Perfusion: In Vivo Methodology and Control by Endothelins

ABSTRACT

Considerable attention has recently been focused on the phenomenon of active constriction of sinusoids as a mechanisms for regulating perfusion of the liver. Although many methods for estimating liver blood flow have been used in the past, the ability to directly study vascular responses in the sinusoids required the spatial and temporal resolution provided by intravital microscopy. Although techniques for viewing microvessels in thin tissues such as the mesentery or cremaster muscle have been available for many years, our current ability to fully use intravital microscopy to study microvascular responses and related metabolic parameters in thick tissues such as the liver has resulted from recent advances in fluorescence microscopy. Intravital microscopy can be used in in vivo or isolated perfused liver studies to assess changes in sinusoidal perfusion. Additional information concerning the relationship between microvascular changes and metabolic parameters in the liver can be simultaneously obtained by exploiting various recent advances in the design of fluorescent indicators. These techniques have allowed the mechanisms regulating sinusoid perfusion to be studied in great detail. It is now clear that sinusoids constrict in vivo in a graded and reversible manner in response to specific mediators such as endothelins. This constriction is modulated by dilators such as nitric oxide and carbon monoxide, which are also generated within the sinusoids. It is likely that poorly regulated sinusoid constriction contributes to liver injury and long-term development of increased intrahe-patic vascular resistance. This response is mediated by alterations in the expression of endothelin receptor subtypes and eventually by phenotypic transformation of the hepatic stellate cells. In addition, local mismatch in the stress-induced induction of vasodilator and vasoconstrictor influences lead to an increase in the local heterogeneity of blood flow and oxygen supply. This heterogeneous perfusion contributes to the development of focal ischemia and progression of injury. Taken together, the results reviewed here indicate that the sinusoid is an important site of regulation of liver blood flow and that dysregulation of sinusoidal perfusion leads to propagation of liver injury.

KEY WORDS

hepatic sinusoids - endothelins - endothelin receptors - intravital microscopy