Relaxin is a peptide hormone emanating from the corpus luteum of the ovary which circulates during pregnancy. Traditionally, the hormone has been associated with female reproductive processes but recent evidence has suggested relaxin may play a vital role in regulating renal and cardiovascular function. Analogous to pregnancy, chronic administration of recombinant human relaxin (rhRLX) to nonpregnant female or male rats induces renal vasodilation and hyperfiltration, as well as reduces the myogenic reactivity of small renal arteries. Additionally, elimination of circulating relaxin in pregnant rats using relaxin neutralizing antibodies or ovariectomy prevents the pregnancy associated changes in the renal circulation.
Based on these findings we postulated that relaxin exerts similar vasodilatory effects in the systemic circulation. We conducted several studies examining the role of relaxin in modulating systemic hemodynamics and vascular wall mechanical properties. Analogous to pregnancy, administration of rhRLX to nonpregnant female or male (normotensive and hypertensive) rats elicited increases in cardiac output and global arterial compliance, as well a decrease in systemic vascular resistance. By neutralizing circulating relaxin in midpregnant rats with specific antibodies, we determined that the hormone was essential for the transition of the systemic circulation from the virgin to the pregnant state.
In order to understand the mechanistic bases for relaxin-induced increase in global arterial compliance, we examined the hormones effects on vascular wall geometric and compositional remodeling. From a geometric perspective, small renal arteries isolated from rhRLX-treated rats and mice were characterized by larger arterial wall area when compared to control counterparts. This resulted primarily from a relaxin-mediated increase in smooth muscle cell hyperplasia, as indicated by increased smooth muscle cell density, not hypertrophy. From a compositional perspective, these arteries were characterized by decreased collagen with no change in elastin content. In contrast, external iliac arteries from rhRLX-treated mice did not exhibit any alterations in biochemical composition or smooth muscle cell density when compared to control mice. Comparable results were observed in relaxin knock-out (Rlx-/-) and wild-type (Rlx+/+) mice, with small renal arteries from Rlx-/- mice exhibiting increased arterial collagen and decreased smooth muscle cell density. Finally, from a tissue mechanics perspective, small renal arteries from rhRlx-treated mice exhibited a strain-dependent reduction in tissue strain energy such that the greatest reduction was observed at the highest circumferential and axial strains.
We conclude relaxin exerts systemic vasodilatory effects in both pregnant and nonpregnant states and in a gender-independent manner. Our findings indicate that the relaxin-induced increase in global arterial compliance is, at least in part, due to vascular wall compositional and geometric remodeling. Further, the vascular wall remodeling effects of relaxin appear to be artery-type specific. Finally, our data indicate that the relaxin-induced compositional remodeling of small renal arteries contributes to tissue mechanical properties under conditions of high circumferential and axial loads.
| Identifer | oai:union.ndltd.org:PITT/oai:PITTETD:etd-05052008-142436 |
| Date | 08 September 2008 |
| Creators | Debrah, Dan Onwona |
| Contributors | Sanjeev G. Shroff, Ph.D., Kirk P. Conrad, M.D., Pamela A. Moalli, M.D., Ph.D., Michael S. Sacks, Ph.D., David A. Vorp, Ph.D. |
| Publisher | University of Pittsburgh |
| Source Sets | University of Pittsburgh |
| Language | English |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | http://etd.library.pitt.edu/ETD/available/etd-05052008-142436/ |
| Rights | restricted, I hereby certify that, if appropriate, I have obtained and attached hereto a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted is the same as that approved by my advisory committee. I hereby grant to University of Pittsburgh or its agents the non-exclusive license to archive and make accessible, under the conditions specified below, my thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report. |
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