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

7. CONCLUSION AND FURTHER DIRECTIONS

During the past ten years we have acquired a greater understanding of some of the early events following AVP binding to its receptor in VSMC. Many of the relevant molecules have been cloned including the AVP receptors and the G-proteins to which it couples. Our current understanding of AVP-mediated signaling in VSMC is depicted in figure 2. A critical event mediating the contractile responses to AVP in these cells is the increase in [Ca²⁺]i, which subsequently activates a number of Ca²⁺ dependent pathways. This increase in Ca²⁺ involves both mobilization of intracellular stores, as well as entry of extracellular Ca²⁺ via cation channels. Sophisticated techniques have examined the kinetics and spatial distribution of Ca²⁺ in great detail, and further progress will be achieved in the next several years. The mechanisms determining contractile sensitivity as well as events controlling the "latch state" are less well understood. It is likely that a critical biological response such as contraction is controlled by multiple mechanisms.

Longer term exposure of VSMC to AVP or other vasoconstrictors has important effects on the growth and differentiation of these cells. Activation of a number of kinase pathways is involved in the induction of families of genes, including immediate early response genes, as well as muscle specific genes. The former family of genes including c-fos, are also induced by mitogenic stimuli such as PDGF. However, the induction of muscle-specific genes is a selective effect of vasoconstrictors, and is in fact antagonized by PDGF. As such understanding the molecular events mediating this induction appears to be a fruitful area for further research. Elucidating events mediating control of muscle specific genes in VSMC will increase our knowledge of control of differentiation. This has direct relevance to pathophysiologic states such as atherosclerosis, where VSMC in the neointima manifest many of the characteristics of the embryonic or proliferative phenotype. By working back from events occurring at the level of muscle-specific promoters such as the SM-alpha-actin promoter, we will reveal pathways that are differently engaged by AVP compared to complete mitogens such as PDGF. These pathways are presumably critical to the hypertrophic response seen with this agent. Much of the focus here will be on downstream events intermediate between the early stimulation of phospholipases and MAP kinase family members, and subsequent activation of specific transcription factors. Two potential attractive candidates are the cytoplasmic tyrosine kinases such as src, and the low molecular weight G-proteins of the Rho, Rac and cdc42 family (130) . These molecules have already been implicated in control of cytoskeletal function (131, 132). In addition to elucidating the signaling pathways regulated by AVP, these studies will in a broader context help define pathways mediated by other hormones which engage Gq proteins.

Finally, it is becoming apparent that there is greater heterogeneity among VSMC in vivo, with multiple cell populations that can be distinguished by differential expression of smooth muscle markers (12). Recently, these distinct populations have been isolated in culture and show distinct phenotypic features and proliferative responses (133). The effects of AVP as well as other agonists is likely to be cell type specific, with functional AVP receptors likely to be expressed on only a subpopulation of these cells. Since most of the studies described in this article have employed preparations which are a mixture of distinct cell types, it may be necessary to revisit the actions of AVP in individual cell populations.