This Article Full Text Full Text (PDF) Data Supplement All Versions of this Article: 93/12/1249    most recent 01.RES.0000104086.43830.6Cv1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Jeyabalan, A. Articles by Conrad, K. P. Search for Related Content PubMed PubMed Citation Articles by Jeyabalan, A. Articles by Conrad, K. P. Related Collections Endothelium/vascular type/nitric oxide Other Research

(Circulation Research. 2003;93:1249.)
© 2003 American Heart Association, Inc.

Integrative Physiology

Essential Role for Vascular Gelatinase Activity in Relaxin-Induced Renal Vasodilation, Hyperfiltration, and Reduced Myogenic Reactivity of Small Arteries

Arundhathi Jeyabalan^*, Jacqueline Novak^*, Lee A. Danielson^*, Laurie J. Kerchner, Shannon L. Opett, Kirk P. Conrad

From the Department of Obstetrics, Gynecology and Reproductive Sciences (A.J., J.N., L.J.K., S.L.O., K.P.C.), University of Pittsburgh School of Medicine and Magee-Women’s Research Institute, Pittsburgh, Pa; Department of Pathology (L.A.D.), University of New Mexico School of Medicine, Albuquerque, NM; Department of Cell Biology and Physiology (K.P.C.), University of Pittsburgh School of Medicine, Pittsburgh, Pa.

Correspondence to Kirk P. Conrad, Magee-Women’s Research Institute, 204 Craft Ave, Pittsburgh, PA 15213. E-mail rsikpc{at}mwri.magee.edu

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.

Key Words: nitric oxide • endothelin B receptor • pregnancy • renal circulation • matrix metalloproteinases

This article has been cited by other articles:

				C. S. Samuel, T. D. Hewitson, Y. Zhang, and D. J. Kelly Relaxin Ameliorates Fibrosis in Experimental Diabetic Cardiomyopathy Endocrinology, July 1, 2008; 149(7): 3286 - 3293. [Abstract] [Full Text] [PDF]

				M. Hladunewich, S. A. Karumanchi, and R. Lafayette Pathophysiology of the Clinical Manifestations of Preeclampsia Clin. J. Am. Soc. Nephrol., May 1, 2007; 2(3): 543 - 549. [Full Text] [PDF]

				A. Jeyabalan, J. Novak, K. D. Doty, J. Matthews, M. C. Fisher, L. J. Kerchner, and K. P. Conrad Vascular Matrix Metalloproteinase-9 Mediates the Inhibition of Myogenic Reactivity in Small Arteries Isolated from Rats after Short-Term Administration of Relaxin Endocrinology, January 1, 2007; 148(1): 189 - 197. [Abstract] [Full Text] [PDF]

				J. Z. He, A. Quan, Y. Xu, H. Teoh, G. Wang, J. E. Fish, B. M. Steer, S. Itohara, P. A. Marsden, S. T. Davidge, et al. Induction of matrix metalloproteinase-2 enhances systemic arterial contraction after hypoxia Am J Physiol Heart Circ Physiol, January 1, 2007; 292(1): H684 - H693. [Abstract] [Full Text] [PDF]

				J. Novak, L. J. Parry, J. E. Matthews, L. J. Kerchner, K. Indovina, K. Hanley-Yanez, K. D. Doty, D. O. Debrah, S. G. Shroff, and K. P. Conrad Evidence for local relaxin ligand-receptor expression and function in arteries FASEB J, November 1, 2006; 20(13): 2352 - 2362. [Abstract] [Full Text] [PDF]

				D. O. Debrah, J. Novak, J. E. Matthews, R. J. Ramirez, S. G. Shroff, and K. P. Conrad Relaxin Is Essential for Systemic Vasodilation and Increased Global Arterial Compliance during Early Pregnancy in Conscious Rats Endocrinology, November 1, 2006; 147(11): 5126 - 5131. [Abstract] [Full Text] [PDF]

				M. C. Smith, Lee. A. Danielson, Kirk. P. Conrad, and J. M. Davison Influence of Recombinant Human Relaxin on Renal Hemodynamics in Healthy Volunteers J. Am. Soc. Nephrol., November 1, 2006; 17(11): 3192 - 3197. [Abstract] [Full Text] [PDF]

				J. D. Silvertown, J. S. Walia, A. J. Summerlee, and J. A. Medin Functional Expression of Mouse Relaxin and Mouse Relaxin-3 in the Lung from an Ebola Virus Glycoprotein-Pseudotyped Lentivirus via Tracheal Delivery Endocrinology, August 1, 2006; 147(8): 3797 - 3808. [Abstract] [Full Text] [PDF]

				A. Jeyabalan, L. J. Kerchner, M. C. Fisher, J. T. McGuane, K. D. Doty, and K. P. Conrad Matrix metalloproteinase-2 activity, protein, mRNA, and tissue inhibitors in small arteries from pregnant and relaxin-treated nonpregnant rats J Appl Physiol, June 1, 2006; 100(6): 1955 - 1963. [Abstract] [Full Text] [PDF]

				A. Khandoga, J. S. Kessler, M. Hanschen, A. G. Khandoga, D. Burggraf, C. Reichel, G. F. Hamann, G. Enders, and F. Krombach Matrix metalloproteinase-9 promotes neutrophil and T cell recruitment and migration in the postischemic liver J. Leukoc. Biol., June 1, 2006; 79(6): 1295 - 1305. [Abstract] [Full Text] [PDF]

				L. A. Danielson, A. Welford, and A. Harris Relaxin Improves Renal Function and Histology in Aging Munich Wistar Rats J. Am. Soc. Nephrol., May 1, 2006; 17(5): 1325 - 1333. [Abstract] [Full Text] [PDF]

				L. J. Kerchner, J. Novak, K. Hanley-Yanez, K. D. Doty, L. A. Danielson, and K. P. Conrad Evidence against the Hypothesis that Endothelial Endothelin B Receptor Expression Is Regulated by Relaxin and Pregnancy Endocrinology, June 1, 2005; 146(6): 2791 - 2797. [Abstract] [Full Text] [PDF]

				D. O. Debrah, K. P. Conrad, L. A. Danielson, and S. G. Shroff Effects of relaxin on systemic arterial hemodynamics and mechanical properties in conscious rats: sex dependency and dose response J Appl Physiol, March 1, 2005; 98(3): 1013 - 1020. [Abstract] [Full Text] [PDF]

				K. P. Conrad Mechanisms of Renal Vasodilation and Hyperfiltration During Pregnancy Reproductive Sciences, October 1, 2004; 11(7): 438 - 448. [Abstract] [PDF]

				J. M. Davison, V. Homuth, A. Jeyabalan, K. P. Conrad, S. A. Karumanchi, S. Quaggin, R. Dechend, and F. C. Luft New Aspects in the Pathophysiology of Preeclampsia J. Am. Soc. Nephrol., September 1, 2004; 15(9): 2440 - 2448. [Abstract] [Full Text] [PDF]

				K. P. Conrad and J. Novak Emerging role of relaxin in renal and cardiovascular function Am J Physiol Regulatory Integrative Comp Physiol, August 1, 2004; 287(2): R250 - R261. [Abstract] [Full Text] [PDF]

				J. Novak, A. Rajakumar, T. M. Miles, and K. P. Conrad Nitric Oxide Synthase Isoforms in the Rat Kidney During Pregnancy Reproductive Sciences, July 1, 2004; 11(5): 280 - 288. [Abstract] [PDF]

				K. P. Conrad, D. O. Debrah, J. Novak, L. A. Danielson, and S. G. Shroff Relaxin Modifies Systemic Arterial Resistance and Compliance in Conscious, Nonpregnant Rats Endocrinology, July 1, 2004; 145(7): 3289 - 3296. [Abstract] [Full Text] [PDF]

				O. D. Sherwood Relaxin's Physiological Roles and Other Diverse Actions Endocr. Rev., April 1, 2004; 25(2): 205 - 234. [Abstract] [Full Text] [PDF]