Abstract
Microparticles are small fragments of the plasma membrane generated after cell stimulation. We recently showed that Sonic hedgehog (Shh) is present in microparticles generated from activated/apoptotic human T lymphocytes and corrects endothelial injury through nitric oxide (NO) release. This study investigates whether microparticles bearing Shh correct angiotensin II-induced hypertension and endothelial dysfunction in mice. Male Swiss mice were implanted with osmotic minipumps delivering angiotensin II (0.5 mg/kg/day) or NaCl (0.9%). Systolic blood pressure and heart rate were measured daily during 21 days. After 7 day of minipump implantation, mice received i.v. injections of microparticles (10 µg/ml) or i.p. Shh receptor antagonist cyclopamine (10 mg/kg/2 days) during one week. Angiotensin II induced a significant rise in systolic blood pressure without affecting heart rate. Microparticles reversed angiotensin II-induced hypertension, and cyclopamine prevented the effects of microparticles. Microparticles completely corrected the impairment of acetylcholine- and flow-induced relaxation in vessels from angiotensin II-infused mice. The improvement of endothelial function induced by microparticles was completely prevented by cyclopamine treatment. Moreover, microparticles alone did not modify NO and O2 . - production in aorta, but significantly increased NO and reduced O2 . - productions in aorta from angiotensin II-treated mice, and these effects were blocked by cyclopamine. Altogether, these results show that microparticles bearing Shh correct angiotensin II-induced hypertension and endothelial dysfunction in aorta through a mechanism associated with Shh-induced NO production and reduction of oxidative stress. These microparticles may represent a new therapeutic approach in cardiovascular diseases associated with decreased NO production.
Highlights
Angiotensin II (Ang II), the principal effector peptide of the renin-angiotensin system, plays a major role in the initiation and progression of vascular diseases, such as hypertension, in part through reactive oxygen species [1]
Endothelial dysfunction in mouse coronary artery after ischemia/reperfusion can be prevented by treatment with Sonic hedgehog (Shh)-carrying MPs [5]
Systolic blood pressure was stable throughout the duration of the experimentation in control mice infused with saline and in those treated either with MPs alone or cyclopamine (Figure 1A)
Summary
Angiotensin II (Ang II), the principal effector peptide of the renin-angiotensin system, plays a major role in the initiation and progression of vascular diseases, such as hypertension, in part through reactive oxygen species [1]. Ang II-induced increase in reactive oxygen species in particular, superoxide (O2·-), leads to decreased bioavailability of nitric oxide (NO), which impairs endothelium-dependent vasodilatation and promotes vasoconstriction. Ang II-induced increase in blood pressure, vascular O2·- levels, and endothelial dysfunction are improved either upon blockade of the system and/or the prevention of oxidative stress leading to an increase of NO bioavailability [2]. We have demonstrated that MPs released by apoptotic/stimulated human T lymphocytes harbor the morphogen Sonic hedgehog (Shh) and improve endothelial function in the mouse aorta by increasing NO release [5]. Endothelial dysfunction in mouse coronary artery after ischemia/reperfusion can be prevented by treatment with Shh-carrying MPs [5]. The present study further aims to investigate whether MPs bearing Shh may correct Ang II-induced hypertension and endothelial dysfunction in mice
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