Vascular Matrix Metalloproteinase-9 Mediates the Inhibition of Myogenic Reactivity in Small Arteries Isolated from Rats after Short-Term Administration of Relaxin

Abstract

During pregnancy and chronic relaxin administration to nonpregnant rats (for days), vascular MMP (matrix metalloproteinase)-2 is increased and mediates renal vasodilation, hyperfiltration, and inhibition of myogenic reactivity of small renal arteries. However, the renal vasodilatory actions of relaxin also occur after only several hours of hormone administration to nonpregnant rats, and we hypothesized a pivotal role for vascular MMP-2. Accordingly, we used gelatin zymography, which reveals not only vascular MMP-2, but also MMP-9 activity in small renal arteries isolated from rats administered recombinant human relaxin (rhRLX) or vehicle for 4 -6 h. Furthermore, we tested whether myogenic reactivity is inhibited, and if so, whether the inhibition is mediated by increased vascular MMP-2. Surprisingly, we detected no significant difference in either pro or active MMP-2 in small renal arteries isolated from rhRLX and vehicle control treatment groups. In contrast, vascular MMP-9 was up-regulated by 70% (P < 0.0005 vs. vehicle). These results were completely unexpected and novel. MMP-9 protein expression was confined to the vascular smooth muscle. MMP-9, but not MMP-2 activity, was also increased in mesenteric arteries after shortterm rhRLX administration (P < 0.005 and >0.05 vs. vehicle, respectively). Myogenic reactivity was inhibited in small renal arteries isolated from nonpregnant rats treated with rhRLX for 4 -6 h (P < 0.01 vs. vehicle) and was completely restored by incubation with MMP-9, but not MMP-2 neutralizing antibodies in vitro. Conclusion: In contrast to chronic rhRLX administration, MMP-9 rather than MMP-2 plays a central role in the vasodilatory effect of short-term relaxin administration. (Endocrinology 148: 189 -197, 2007) O NE OF THE earliest and most dramatic adaptations to pregnancy is dilation of the maternal vasculature. The gravid rat model has been used extensively to investigate this circulatory adaptation that is comparable to human pregnancy (1-3). Pregnancy mediates renal vasodilation, hyperfiltration and reduced myogenic reactivity via the endothelial ET B (endothelin) receptor subtype-nitric oxide pathway (4 -6). During pregnancy, the ovarian hormone, relaxin (RLX) stimulates this vasodilatory pathway and when chronically administered to nonpregnant rats mimics the pregnant condition (7-11).We have recently shown that relaxin up-regulates vascular gelatinase activity during pregnancy, thereby mediating renal vasodilation, hyperfiltration, and loss of myogenic reactivity in small renal arteries through processing of big ET to ET 1-32 , which activates the endothelial ET B receptor-nitric oxide pathway (12). During pregnancy and after chronic (5 d) relaxin administration to nonpregnant rats, vascular matrix metalloproteinase (MMP)-2 is specifically implicated in these renal circulatory changes (12). Vascular MMP-2 activity is increased in these small renal and mesenteric arteries as a consequence of increased MMP-2 mRNA and protein expression (13).To mimic the renal hemodynamic change...

Relaxin Therapy Reverses Large Artery Remodeling and Improves Arterial Compliance in Senescent Spontaneously Hypertensive Rats

“…Thus, a stiffer large artery in senescent SHRs is largely attributable to increased collagen content in the vascular matrix, and relaxin improves arterial compliance largely through its collagen-lowering action. Reduction in vascular collagen by relaxin treatment is most likely attributable to increased breakdown of collagen after increment in matrix metalloproteinase levels, as shown by studies from Jeyabalan et al 27 We did not determine matrix metalloproteinase levels, considering the fact that aorta samples were collected 7 days after termination of relaxin treatment.…”

“…Vascular actions of relaxin have been well described. 1 Conrad and colleagues 1,7,10,26,27 have conducted a series of studies documenting vasodilatation and arterial pressurelowering action of relaxin of exogenous or endogenous sources. Relaxin levels in pregnant rodents increase markedly together with the development of more compliant arteries, leading to the notion that endogenous relaxin plays a key role in the hemodynamic adjustment during pregnancy.…”

Matrix metalloproteinase-9 polymorphisms affect plasma MMP-9 levels and antihypertensive therapy responsiveness in hypertensive disorders of pregnancy

“…In vitro studies showed that the 'C' to 'T' substitution at À1562 position increases MMP-9 expression. 17 However, the (CA) 14 allele causes a 50% reduction in MMP-9 promoter activity as compared with the (CA) 21 . 18,19 Interestingly, these polymorphisms may affect drug responses 20 and both polymorphisms have been associated with PE or GH, 21,22 thus suggesting that MMP-9 genetic variations may predispose to hypertensive disorders of pregnancy.…”

“…[6][7][8][9][10] Specifically, MMP-9 may be involved in placental and uterine arterial remodeling 11,12 and in the control of the vascular tone. 13,14 In addition, there is evidence that MMPs interact with oxidative stress and inflammatory mediators contributing to the endothelial dysfunction of PE patients. 15 Therefore, the involvement of MMPs in the vascular alterations of hypertensive disorders of pregnancy may aggravate the lack of responses to antihypertensive therapy in some patients.…”

Metalloproteinases: key and common mediators of multiple GPCRs and candidate therapeutic targets in models of hypertensive cardiac disease

“…For instance, MMP-2 and MMP-9 can acutely enhance vascular tone through the cleavage of vasoactive peptides such as adrenomedullin, calcitonin gene-related peptide and big endothelin-1 [16,[33][34][35]. Another non-ECM acute action of MMPs and ADAMs is shedding of membrane-anchored ligands of receptors such as epidermal growth factor (EGF) and platelet-derived growth factor (PDGF) to transactivate intracellular signaling of growth via the MAPK cascade.…”