VASCULAR ENDOTHELIAL GROWTH FACTOR (VEGF) IS A NEW PLAYER IN THE SLOW RELAXIN (Rlx) VASODILATORY PATHWAY

The vasodilatory mechanisms of Rlx depend on duration of hormone exposure. After hour(s) or day(s) of Rlx administration to rats, vascular gelatinase MMP‐2 or ‐9, respectively, increases which processes big (endothelin) ET to ET 1–32 that, in turn, activates the endothelial ET B receptor/NO vasodilatory pathway. We hypothesized that these slow vasodilatory responses to Rlx require cross‐talk involving VEGF (VSM → EC), in addition to NO (EC → VSM). Small rat renal and human subcutaneous arteries were mounted in a pressure arteriograph. Myogenic reactivity was inhibited after incubation with 30 ng/ml Rlx for 3 h, and restored by subsequent treatment with 0.1 mM L‐NMA, 10 μM RES‐701‐1 (an ET B receptor antagonist) or 1 μM GM6001 (a general MMP inhibitor). Pre‐treatment of rat renal arteries with the VEGF receptor tyrosine kinase inhibitor, 3μM SU5416 (p<0.004 vs dilute DMSO vehicle) or 3 μg/ml VEGF neutralizing antibody (p<0.002 vs goat IgG) prevented the loss of myogenic reactivity by Rlx. In contrast, post‐treatment with SU5416 did not block Rlx action. In preliminary studies, pre‐treatment with either SU5416 or VEGF neutralizing antibody also prevented the loss of myogenic activity by Rlx in human subcutaneous arteries. Conclusions: Incubation of small arteries with Rlx inhibits myogenic reactivity via a vascular MMP/ET B /NO pathway; VEGF is a new player that is most likely in series with, and upstream of, vascular gelatinase.