ARTERIAL NERVE GROWTH-FACTOR (NGF) MESSENGER-RNA, PROTEIN, AND VASCULAR SMOOTH-MUSCLE CELL NGF SECRETION IN HYPERTENSIVE AND HYPERACTIVE RATS

levels of nerve growth factor (NGF) protein and NGF mRNA have been rep orted in the vessels of spontaneously hypertensive rats (SHR: hyperten sive, hyperactive) compared to Wistar-Kyoto (WKY) rats, Elevated NGF m ay be involved in the development of hypertension in SHRs. We examined vascular NGF mRNA and protein content and the regulation of NGF secre tion by vascular smooth muscle cells (VSMCs) from two inbred strains ( WKHT: hypertensive; WKHA: hyperactive) derived from SHRs and WKYs. Our goal was to determine if receptor-mediated defects in NGF regulation play a role in increased secretion of VSMC NGF from hypertensive anima ls. Tissue NGF mRNA content was determined by competitive, quantitativ e RT-PCR. Tissue NGF and NGF content in cultured VSMC-conditioned medi um was quantified using a two-site ELISA. Tail artery NGF mRNA was ele vated in WKHTs compared to WKHAs. Tissue NGF protein was elevated in W KHT aorta, mesenteric, and tail artery compared to WRHAs, Pharmacologi cally induced increases in NGF output were blocked with inhibition of transcription or protein synthesis. Basal NGF secretion by WKHT VSMCs was significantly higher than WKHAs. The observed increases in VSMC NG F output in SHRs over WKYs in response to beta-adrenergic agents are n ot preserved in the WKHT:WKHA comparison, Protein kinase C-dependent i ncreases in SHR VSMC NGF appear in both WKHTs and WKHAs. In contrast, elevated NGF levels due to disturbances in alpha-adrenergic, peptiderg ic, and purinergic control of NGF output are features common to both g enetic models of hypertension (SHR and WKHT). These results suggest th at the defect in smooth muscle NGF metabolism observed in SHRs cosegre gates with a hypertensive rather than a hyperactive phenotype. Moreove r, altered receptor-mediated regulation (alpha-adrenergic, peptidergic , and purinergic) of VSMC NGF production may contribute to elevated va scular tissue NGF, suggesting a mechanism leading to the high levels o f NGF associated with hypertension in SHRs and WKHTs. (C) 1998 Academi c Press.