Stretch-activated signaling of nerve growth factor secretion in bladder and vascular smooth muscle cells from hypertensive and hyperactive rats

Elevated vascular (VSMC) and bladder smooth muscle (BSMC) NGF are associate d with altered visceral innervation in the spontaneously hypertensive rat ( SHR: hypertensive, behaviorally hyperactive) compared with control Wistar-K yotos (WKYs). Stretch stimulates increased NGF production in BSMCs. To eluc idate whether stretch induces NGF synthesis in VSMCs, and to determine if d isturbances in stretch-mediated NGF production contribute to the elevated t issue levels of NGF in SHRs, we subjected VSMCs and BSMCs cultured from fou r established inbred rat strains (WKY, WKHA: hyperactive; SHR and WKHT: hyp ertensive) to several stretch paradigms. For VSMCs, acute and cyclic stretc h affected cells derived from hypertensive rats (80-100% increase over cont rol) but not from normotensive strains. For BSMCs, cyclic and static stretc h increased NGF secretion in all four strains, but had a two- to threefold greater effect in cells from SHRs and WKHTs (increase up to 600%) at early time points. At later time points of a 24-h experimental period, stretch in creased NGF output up to 400% in SHR and WKHA cultures. Thus, defects that influence early induction of stretch-mediated SHR NGF secretion cosegregate with the hypertensive phenotype. Stretch-gated ion channel inhibitors, vol tage-gated ion channel inhibitors, and protease inhibitors failed to affect stretch-induced BSMC NGF secretion. In contrast, gene transcription, intra cellular calcium, protein kinase C (PKC), and autocrine release of an unkno wn factor may play a role in the elevated NGF secretion observed in smooth muscle from hypertensive animals. Altered stretch-induced smooth muscle NGF secretion may contribute to the augmented vascular and bladder NGF content associated with high blood pressure and hyperactive voiding in SHRs. J. Ce ll. Physiol. 183:289-300, 2000 (C) 2000 Wiley-Liss, Inc.