VASOPRESSIN SIGNALING PATHWAYS IN VASCULAR SMOOTH MUSCLE

Raphael A. Nemenoff

Department of Medicine, University of Colorado Health Sciences Center, Denver, CO 80262

Received 1/21/98 Accepted 2/4/98

2. INTRODUCTION

Arginine vasopressin (AVP1) plays a major role in the regulation of body fluid volume and the maintenance of blood pressure. The biological effects of AVP are mediated through cell-surface receptors which have been divided into two classes. The renal receptor, designated V2, has been shown to be involved in water reabsorption, and is coupled to adenylyl cyclase. The vascular receptor has been designated V1a, and is expressed in vascular smooth muscle and liver. A third vasopressin receptor, designated V1b, appears to be selectively expressed in pituitary cells. All of these receptors have recently been cloned (1, 2, 3), and belong to the family of "seven membrane spanning" receptors which signal through G-proteins. Non-peptide antagonists have been developed which selectively block individual receptor isoforms (4, 5, 6, 7), allowing assessment of the contributions of these different receptors in different cell types. Following AVP binding, cells undergo homologous desensitization within minutes (8). AVP-receptors are internalized from the cell surface and recycled (9). The role of receptor internalization in AVP signaling remains controversial. Recent studies have indicated that receptor internalization of other receptors signaling through G-proteins is critical for activation of some signaling pathways (10). This has not to date been examined for the V1a receptor in VSMC.

In vascular smooth muscle, AVP has been shown to be a potent vasoconstrictor, both in vivo, and in cultured cell preparations. Increases in contractile force are observed within seconds to minutes following exposure to the hormone, and are mediated via the V1a receptor (11). Perhaps less appreciated is the fact that long-term exposure of vascular smooth muscle cells (VSMC) to AVP promotes the growth of these cells and regulates patterns of gene expression. While it is highly likely that both the acute and the long-term effects are mediated through the V1 receptor, the G-proteins and downstream effectors leading to these pleiotropic responses have only recently begun to be identified. Numerous early signaling events have been described during the past several years. However, linking activation of specific pathways to distinct physiologic responses still represents "work in progress". The goal of this manuscript is to review our current knowledge of post-receptor signaling pathways known to be regulated by AVP in VSMC. The majority of the studies described have been performed in cultured vascular smooth muscle cells. We will briefly describe the physiologic effects of AVP in early passage cells as well as a number of established cell lines which are being used by investigators in this area. Subsequently specific effector systems will be examined. Where data exists, we will attempt to assign a physiologic role to these pathways in mediating the actions of AVP. However, a cautionary disclaimer should be added, which can be applied to other studies on signal transduction. In vivo, the responses of vascular smooth muscle cells will reflect a complex interaction from multiple inputs including circulating factors, extracellular matrix, and interaction with other cell types, such as endothelial cells. The work described in this review therefore represent a partial, but growing list of potentially important pathways whose role in vivo will need to be studied directly. It is also becoming apparent that VSMC within the vessel wall are not homogenous, and distinct subpopulations have been isolated (12). These cells may well exhibit heterogeneous response to AVP as well as other agonists, and information obtained from "standard" preparations of VSMC may need to be reexamined in phenotypically homogenous preparations.