Elsevier

Peptides

Volume 30, Issue 6, June 2009, Pages 1117-1123
Peptides

Urocortin inhibits mesenteric arterial remodeling in spontaneously hypertensive rats

https://doi.org/10.1016/j.peptides.2009.02.014Get rights and content

Abstract

Urocortin (UCN), a newly isolated corticotrophin-releasing factor (CRF) related peptide, has been found to have potent cardiovascular protective effects. This study aimed to investigate the long-term effects of UCN on arterial remodeling and related functional alterations. UCN (7 μg/kg/d) was administered to spontaneously hypertensive rats (SHR) for 8 weeks. Systolic blood pressure (SBP) was measured weekly. Functional studies were performed on isolated mesenteric arterial segments. Also, by light microscope and electron microscope, the morphology of mesenteric arteries was examined. Our results showed that mean SBP in UCN-treated SHRs was about 40 mmHg lower than that of the control SHR group, and was similar to that of the enalapril-treated group. In the mesenteric arterial segments pre-contracted with norepinephrine (0.001–10 μM), the maximal relaxation rate induced by acetylcholine (10 μM) in UCN-treated group (about 93.3%) was higher than that in SHR control group (about 40.0%) (n = 6, P < 0.01). Furthermore examination under light microscope showed that UCN (3.5 μg/kg/d) treatment significantly reduced media thickness, media/lumen ratio, resulting in larger lumen diameter while analysis of transmission electron microscopic findings revealed that chromatin, internal elastic lamina and densely packed mitochondria displayed a close-to-normal distribution after UCN treatment. These results suggested that long-term UCN treatment not only had hypotensive effects but may also inhibited development of vascular remodeling in mesenteric arteries in SHR.

Introduction

Urocortin (UCN), a 40-amino acid peptide, has 45% structural homology with the peptide corticotrophin-releasing factor (CRF) and belongs to a group of structurally related peptides which include, in addition to UCN and CRF, urotensin1 and sauvagine [5], isolated from fish neurosecretory cell and frog skin, respectively. Immunoreactivity study showed that UCN is widely distributed in central nervous, digestive, cardiovascular, reproductive, immune, and endocrine systems [24], [35]. These facts suggested that UCN may have important physiological roles in various tissues.

In addition to pituitary and central effects as neurotransmitters, peripheral effects of CRF-related peptides have been observed, particularly in the cardiovascular system in which UCN exerts cardioprotective effect. In cardiac system, in vitro studies have demonstrated that UCN can protect neonatal rat cardiac myocytes when administered before hypoxia or at the point of reoxygenation while in adult rat heart UCN reduced the infarct size of a perfused intact rat heart exposed to regional ischemia [3], which was confirmed by our recent in vivo study [17]. Furthermore, a number of studies have implied that the mitogen-activated protein kinase (MAPK) acts as a survival pathway in cardiac cells and other cell types [1], [6], which might be one of the underlying cardioprotective mechanisms of the effects induced by UCN [3], [9].

On the other hand, in normal mice and rats, intravenous administration of UCN caused decrease in blood pressure and improved the contractility of the heart [22] after long-term administration possibly by hindering the development of cardiac remodeling. In vasculature, UCN binds with high affinity to CRF 2 receptor (CRFR2), mediating a vasodilating action [8], [35]. CRFR2, localized at distinct central and peripheral sites has been shown to play an important role in vascular regulation [18], [30]. In rats, UCN was found to produce a potent, long lasting hypotension, which might be due to systemic vasodilation [5]. It has been shown that UCN could cause relaxation of rat basilar [26], tail [19], and coronary arteries [12], and result in a reduction in arterial pressure [25] and an increase in heart rate [23].

In a previous study, UCN was reported to induce both endothelium-dependent and endothelium-independent vascular relaxation [15], highly implying that UCN may affect vascular smooth muscle cells (VSMC) directly. Our in vitro study indicated that UCN could reduce the viability of adult rat VSMC [32]. These results suggest that UCN might play a role in vascular remodeling since VSMC are a key factor in the development of vascular remodeling [2]. So far however, there has been no in vivo investigation about the effects of UCN on vascular remodeling in spontaneously hypertensive rats (SHRs).

This present study deals with the inhibitory effect of UCN on the development of mesenteric arterial remodeling in SHRs. With the model of the rats, we firstly investigated the effects of long-term (56 days) intravenous UCN on the functional and structural changes of mesenteric arteries.

Section snippets

Materials and methods

Animal care and handling conformed to the Guide for Care and Use of Laboratory Animals published by the US National Institutes of Health (NIH), and the study was approved by the local institutional ethical committee.

Effects of UCN on blood pressure

To determine whether UCN could maintain a stable hypotensive action, the rats were treated for 56 days with UCN (1 μg/kg/d, 3.5 μg/kg/d and 7 μg/kg/d), enalapril (10 mg/kg/d), or saline. Before the treatment began, SBP in SHR groups had no significant difference, and was remarkably higher than that in WKY rats (n = 6, P < 0.01) (Table 1). A significant decrease of about 40 mmHg in SBP, which was approximately equivalent for both UCN (7 μg/kg/d) and enalapril, was observed 1 week after the beginning of

Discussion

Hypertension is a critical risk factor for cardiovascular events, and thus the research of the vascular function during hypertension has attracted extensive attention. It is well established that hypertension is always accompanied with increase in artery wall thickness, mainly caused by proliferation, hypertrophy, migration and apoptosis of vascular smooth muscle cells (VSMC) accompanying with elevated content of connective tissues [2]. In general, the resistance vessels of essential

Acknowledgements

This work was supported by grants from Natural Science Foundation of China (No. 30371646) and Key Subject of Ministry of Education of China (No. 03047).

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