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Regulation of Nitric Oxide Production in the Developmental Programming of Hypertension and Kidney Disease
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Int. J. Mol. Sci. 2019, 20(5), 1157;

Nitric Oxide Reverses the Position of the Heart during Embryonic Development

Vascular Biology Lab, AU-KBC Research Centre, Anna University, Chennai, Chennai-600044, India
Department of Molecular Pharmacology, Physiology and Biotechnology, Brown University, Providence, RI 02903, USA
Vascular Research Laboratory, Providence Veterans Affairs Medical Center, Providence, RI 02908, USA
Department of Biotechnology, Anna University, Chennai, Chennai-600025, India
Author to whom correspondence should be addressed.
Received: 29 January 2019 / Revised: 14 February 2019 / Accepted: 18 February 2019 / Published: 7 March 2019
(This article belongs to the Special Issue Nitric Oxide Synthases: Regulation and Function)
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Nitric oxide (NO) produced by endothelial nitric oxide synthase (eNOS) plays crucial roles in cardiac homeostasis. Adult cardiomyocyte specific overexpression of eNOS confers protection against myocardial-reperfusion injury. However, the global effects of NO overexpression in developing cardiovascular system is still unclear. We hypothesized that nitric oxide overexpression affects the early migration of cardiac progenitor cells, vasculogenesis and function in a chick embryo. Vehicle or nitric oxide donor DEAN (500 µM) were loaded exogenously through a small window on the broad side of freshly laid egg and embryonic development tracked by live video-microscopy. At Hamburg Hamilton (HH) stage 8, the cardiac progenitor cells (CPC) were isolated and cell migration analysed by Boyden Chamber. The vascular bed structure and heart beats were compared between vehicle and DEAN treated embryos. Finally, expression of developmental markers such as BMP4, Shh, Pitx2, Noggin were measured using reverse transcriptase PCR and in-situ hybridization. The results unexpectedly showed that exogenous addition of pharmacological NO between HH stage 7–8 resulted in embryos with situs inversus in 28 out of 100 embryos tested. Embryos treated with NO inhibitor cPTIO did not have situs inversus, however 10 embryos treated with L-arginine showed a situs inversus phenotype. N-acetyl cysteine addition in the presence of NO failed to rescue situs inversus phenotype. The heart beat is normal (120 beats/min) although the vascular bed pattern is altered. Migration of CPCs in DEAN treated embryos is reduced by 60% compared to vehicle. BMP4 protein expression increases on the left side of the embryo compared to vehicle control. The data suggests that the NO levels in the yolk are important in turning of the heart during embryonic development. High levels of NO may lead to situs inversus condition in avian embryo by impairing cardiac progenitor cell migration through the NO-BMP4-cGMP axis. View Full-Text
Keywords: nitric oxide; situs inversus; BMP4; CPC migration nitric oxide; situs inversus; BMP4; CPC migration

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Siamwala, J.H.; Kumar, P.; Veeriah, V.; Muley, A.; Rajendran, S.; Konikkat, S.; Majumder, S.; Mani, K.P.; Chatterjee, S. Nitric Oxide Reverses the Position of the Heart during Embryonic Development. Int. J. Mol. Sci. 2019, 20, 1157.

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