Essential Role for Vascular Gelatinase Activity in Relaxin-Induced Renal Vasodilation, Hyperfiltration, and Reduced Myogenic Reactivity of Small Arteries
| Autor: | Shannon L. Opett, Lee A. Danielson, Arundhathi Jeyabalan, Kirk P. Conrad, Jacqueline Novak, Laurie J. Kerchner |
|---|---|
| Rok vydání: | 2003 |
| Předmět: |
Male
medicine.medical_specialty Physiology Vasodilation Endothelin-Converting Enzymes In Vitro Techniques Matrix Metalloproteinase Inhibitors Kidney Peptides Cyclic chemistry.chemical_compound Renal Artery Pregnancy Serelaxin Internal medicine medicine Animals Aspartic Acid Endopeptidases Humans Protease Inhibitors Rats Long-Evans Relaxin Renal circulation Chemistry Phosphoramidon Metalloendopeptidases Dipeptides Recombinant Proteins Rats Endocrinology medicine.anatomical_structure Matrix Metalloproteinase 9 Gelatinases Renal physiology Circulatory system Matrix Metalloproteinase 2 Female Cardiology and Cardiovascular Medicine Oligopeptides Glomerular Filtration Rate Blood vessel |
| Zdroj: | Circulation Research. 93:1249-1257 |
| ISSN: | 1524-4571 0009-7330 |
| DOI: | 10.1161/01.res.0000104086.43830.6c |
| Popis: | During pregnancy, relaxin stimulates nitric oxide (NO)–dependent renal vasodilation, hyperfiltration and reduced myogenic reactivity of small renal arteries via the endothelial ET B receptor subtype. Our objective in this study was to elucidate the mechanisms by which relaxin stimulates the endothelial ET B receptor/NO vasodilatory pathway. Using chronically instrumented conscious rats, we demonstrated that a specific peptide inhibitor of the gelatinases MMP-2 and −9, cyclic CTTHWGFTLC (cyclic CTT), but not the control peptide, STTHWGFTLS (STT), completely reversed renal vasodilation and hyperfiltration in relaxin-treated rats. Comparable findings were observed with a structurally different and well-established, general antagonist of MMPs, GM6001. In contrast, phosphoramidon, an inhibitor of endothelin-converting enzyme, did not significantly change the renal vasodilatory response to relaxin administration. When small renal arteries were incubated with either of the general MMP inhibitors, GM6001 or TIMP-2 (tissue inhibitor of MMP), or with the specific gelatinase inhibitor, cyclic CTT, the reduced myogenic reactivity of these blood vessels from relaxin-treated nonpregnant and midterm pregnant rats was totally abolished. Moreover, a neutralizing antibody specific for MMP-2 completely abrogated the reduced myogenic reactivity of small renal arteries from relaxin-treated nonpregnant and midterm pregnant rats. In contrast, phosphoramidon did not significantly affect the reduction in myogenic reactivity. Using gelatin zymography, we showed increased pro and active MMP-2 activity in small renal arteries from relaxin-treated nonpregnant and midterm pregnant rats relative to the control animals. Thus, inhibitors of MMPs in general and of gelatinases in particular reverse the renal vascular changes induced by pregnancy or relaxin administration to nonpregnant rats. Finally, the typical reduction in myogenic reactivity of small renal arteries from relaxin-treated nonpregnant rats was absent in ET B receptor–deficient rats, despite an increase in vascular MMP-2 activity. These results indicate an essential role for vascular gelatinase, which is in series with, and upstream of, the endothelial ET B receptor/NO signaling pathway in the renal vasodilatory response to relaxin and pregnancy. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|