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

6. OTHER EFFECTORS

AVP and other vasoconstrictors have been shown to rapidly activate the Na⁺/H⁺ exchanger in VSMC (20, 121). In media not containing bicarbonate, activation of this exchanger results in increases in intracellular Na⁺, and alkalinization of the cells. Alkalinization has been associated with mitogenic stimuli; however recent studies have demonstrated that in bicarbonate-containing buffers this phenomenon does not occur (122). The physiologic importance of activation of the Na⁺/H⁺ exchanger therefore remains to be established. It is possible that increased intracellular Na⁺ will regulate intracellular free Ca²⁺ through the Na⁺/Ca²⁺ exchanger. Intracellular Na⁺ levels may also regulate other intracellular pathways.

Intensive interest has recently been focused on nitric oxide as a potent vasodilator and second messenger in vascular cells (see (123) for review). In response to cytokines such as interleukin 1 beta, VSMC increase expression of an inducible form of nitric oxide synthase (iNOS). AVP has been shown to inhibit this induction (124, 125), by inhibiting transcriptional activation. This finding suggests that in addition to directly stimulating contractile pathways, AVP inhibits vasodilatory pathways. Further studies are required to dissect the post-receptor pathways mediating this effect.

A number of studies have examined abnormalities in vasoconstrictor responsiveness of VSMC

Figure 2.AVP Signaling Pathways in VSMC. AVP binds to its receptor, which is coupled to Gq. Gq activates phospholipase C(PLCb), resulting in increased Ca²⁺, via inositol trisphosphate, and activation of protein kinase C (PKC). Gq also increases JNK activity through an unidentified pathway. Increases in Ca²⁺ activate Ca²⁺ dependent enzymes. Via calmodulin (CaM), myosin light chain kinase (MLCK) and Ca²⁺/calmodulin dependent kinases (CMK) are activated. Ca²⁺ also activates cytosolic phospholipase A2 (cPLA2). PKC is critical for ERK activation, which phosphorylates cPLA2 as well as contributing to hypertrophy. JNK activation participates in the positive induction of SM-alpha-actin, a marker for the differentiated phenotype of VSMC.

from SHR rats. Aortic smooth muscle cells from spontaneously hypertensive rats (SHR) rats proliferate more rapidly, and are more numerous at confluency than cells from the control WKY rats (126). In contrast to normal VSMC, angiotensin has been shown to have some mitogenic activity in these cells (127). The magnitude of the Ca²⁺ increase observed after vasoconstrictor stimulation appears to be greater in the SHR rats (128). However, this abnormality in itself does not appear to account for the enhanced proliferation (129). The role of phenotypic state in the responsiveness of VSMC from SHR rats has not been examined and is one area for future research.