Tissue Plasminogen Activator and Plasminogen Activator Inhibitor 1 Contribute to Sonic Hedgehog-Induced In Vitro Cerebral Angiogenesis

The molecular mechanisms underlying cerebral angiogenesis have not been fully investigated. Using primary mouse brain endothelial cells (MBECs) and a capillary-like tube formation assay, we investigated whether the sonic hedgehog (Shh) signaling pathway is coupled with the plasminogen/plasmin system...

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Main Authors:	Teng, Hua, Chopp, Michael, Hozeska-Solgot, Ann, Shen, Lihong, Lu, Mei, Tang, Clark, Zhang, Zheng Gang
Format:	Online
Language:	English
Published:	Public Library of Science 2012
Online Access:	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3303815/

id	pubmed-3303815
recordtype	oai_dc
spelling	pubmed-33038152012-03-19 Tissue Plasminogen Activator and Plasminogen Activator Inhibitor 1 Contribute to Sonic Hedgehog-Induced In Vitro Cerebral Angiogenesis Teng, Hua Chopp, Michael Hozeska-Solgot, Ann Shen, Lihong Lu, Mei Tang, Clark Zhang, Zheng Gang Research Article The molecular mechanisms underlying cerebral angiogenesis have not been fully investigated. Using primary mouse brain endothelial cells (MBECs) and a capillary-like tube formation assay, we investigated whether the sonic hedgehog (Shh) signaling pathway is coupled with the plasminogen/plasmin system in mediating cerebral angiogenesis. We found that incubation of MBECs with recombinant human Shh (rhShh) substantially increased the tube formation in naïve MBECs. This was associated with increases in tissue plasminogen activator (tPA) activation and reduction of plasminogen activator inhibitor 1 (PAI-1). Blockage of the Shh pathway with cyclopamine abolished the induction of tube formation and the effect of rhShh on tPA and PAI-1. Addition of PAI-1 reduced rhShh-augmented tube formation. Genetic ablation of tPA in MBECs impaired tube formation and downregulated of vascular endothelial growth factor (VEGF) and angiopoietin 1 (Ang1). Addition of rhShh to tPA−/− MBECs only partially restored the tube formation and upregulated Ang1, but not VEGF, although rhShh increased VEGF and Ang1 expression on wild-type MBECs. Complete restoration of tube formation in tPA−/− MBECs was observed only when both exogenous Shh and tPA were added. The present study provides evidence that tPA and PAI-1 contribute to Shh-induced in vitro cerebral angiogenesis. Public Library of Science 2012-03-14 /pmc/articles/PMC3303815/ /pubmed/22432023 http://dx.doi.org/10.1371/journal.pone.0033444 Text en Teng et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
repository_type	Open Access Journal
institution_category	Foreign Institution
institution	US National Center for Biotechnology Information
building	NCBI PubMed
collection	Online Access
language	English
format	Online
author	Teng, Hua Chopp, Michael Hozeska-Solgot, Ann Shen, Lihong Lu, Mei Tang, Clark Zhang, Zheng Gang
spellingShingle	Teng, Hua Chopp, Michael Hozeska-Solgot, Ann Shen, Lihong Lu, Mei Tang, Clark Zhang, Zheng Gang Tissue Plasminogen Activator and Plasminogen Activator Inhibitor 1 Contribute to Sonic Hedgehog-Induced In Vitro Cerebral Angiogenesis
author_facet	Teng, Hua Chopp, Michael Hozeska-Solgot, Ann Shen, Lihong Lu, Mei Tang, Clark Zhang, Zheng Gang
author_sort	Teng, Hua
title	Tissue Plasminogen Activator and Plasminogen Activator Inhibitor 1 Contribute to Sonic Hedgehog-Induced In Vitro Cerebral Angiogenesis
title_short	Tissue Plasminogen Activator and Plasminogen Activator Inhibitor 1 Contribute to Sonic Hedgehog-Induced In Vitro Cerebral Angiogenesis
title_full	Tissue Plasminogen Activator and Plasminogen Activator Inhibitor 1 Contribute to Sonic Hedgehog-Induced In Vitro Cerebral Angiogenesis
title_fullStr	Tissue Plasminogen Activator and Plasminogen Activator Inhibitor 1 Contribute to Sonic Hedgehog-Induced In Vitro Cerebral Angiogenesis
title_full_unstemmed	Tissue Plasminogen Activator and Plasminogen Activator Inhibitor 1 Contribute to Sonic Hedgehog-Induced In Vitro Cerebral Angiogenesis
title_sort	tissue plasminogen activator and plasminogen activator inhibitor 1 contribute to sonic hedgehog-induced in vitro cerebral angiogenesis
description	The molecular mechanisms underlying cerebral angiogenesis have not been fully investigated. Using primary mouse brain endothelial cells (MBECs) and a capillary-like tube formation assay, we investigated whether the sonic hedgehog (Shh) signaling pathway is coupled with the plasminogen/plasmin system in mediating cerebral angiogenesis. We found that incubation of MBECs with recombinant human Shh (rhShh) substantially increased the tube formation in naïve MBECs. This was associated with increases in tissue plasminogen activator (tPA) activation and reduction of plasminogen activator inhibitor 1 (PAI-1). Blockage of the Shh pathway with cyclopamine abolished the induction of tube formation and the effect of rhShh on tPA and PAI-1. Addition of PAI-1 reduced rhShh-augmented tube formation. Genetic ablation of tPA in MBECs impaired tube formation and downregulated of vascular endothelial growth factor (VEGF) and angiopoietin 1 (Ang1). Addition of rhShh to tPA−/− MBECs only partially restored the tube formation and upregulated Ang1, but not VEGF, although rhShh increased VEGF and Ang1 expression on wild-type MBECs. Complete restoration of tube formation in tPA−/− MBECs was observed only when both exogenous Shh and tPA were added. The present study provides evidence that tPA and PAI-1 contribute to Shh-induced in vitro cerebral angiogenesis.
publisher	Public Library of Science
publishDate	2012
url	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3303815/
_version_	1611513998658764800

Tissue Plasminogen Activator and Plasminogen Activator Inhibitor 1 Contribute to Sonic Hedgehog-Induced In Vitro Cerebral Angiogenesis

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