HIF-1α promotes cellular growth in lymphatic endothelial cells exposed to chronically elevated pulmonary lymph flow

Abstract Normal growth and development of lymphatic structures depends on mechanical forces created by accumulating interstitial fluid. However, prolonged exposure to pathologic mechanical stimuli generated by chronically elevated lymph flow results in lymphatic dysfunction. The mechanisms that tran...

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Autores principales:	Jason T. Boehme, Catherine J. Morris, Samuel R. Chiacchia, Wenhui Gong, Katherine Y. Wu, Rebecca J. Kameny, Gary W. Raff, Jeffrey R. Fineman, Emin Maltepe, Sanjeev A. Datar
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/21ad722718874b2cb2712a1a9ed64d7b
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spelling	oai:doaj.org-article:21ad722718874b2cb2712a1a9ed64d7b2021-12-02T15:22:58ZHIF-1α promotes cellular growth in lymphatic endothelial cells exposed to chronically elevated pulmonary lymph flow10.1038/s41598-020-80882-12045-2322https://doaj.org/article/21ad722718874b2cb2712a1a9ed64d7b2021-01-01T00:00:00Zhttps://doi.org/10.1038/s41598-020-80882-1https://doaj.org/toc/2045-2322Abstract Normal growth and development of lymphatic structures depends on mechanical forces created by accumulating interstitial fluid. However, prolonged exposure to pathologic mechanical stimuli generated by chronically elevated lymph flow results in lymphatic dysfunction. The mechanisms that transduce these mechanical forces are not fully understood. Our objective was to investigate molecular mechanisms that alter the growth and metabolism of isolated lymphatic endothelial cells (LECs) exposed to prolonged pathologically elevated lymph flow in vivo within the anatomic and physiologic context of a large animal model of congenital heart disease with increased pulmonary blood flow using in vitro approaches. To this end, late gestation fetal lambs underwent in utero placement of an aortopulmonary graft (shunt). Four weeks after birth, LECs were isolated and cultured from control and shunt lambs. Redox status and proliferation were quantified, and transcriptional profiling and metabolomic analyses were performed. Shunt LECs exhibited hyperproliferative growth driven by increased levels of Hypoxia Inducible Factor 1α (HIF-1α), along with upregulated expression of known HIF-1α target genes in response to mechanical stimuli and shear stress. Compared to control LECs, shunt LECs exhibited abnormal metabolism including abnormalities of glycolysis, the TCA cycle and aerobic respiration. In conclusion, LECs from lambs exposed in vivo to chronically increased pulmonary lymph flow are hyperproliferative, have enhanced expression of HIF-1α and its target genes, and demonstrate altered central carbon metabolism in vitro. Importantly, these findings suggest provocative therapeutic targets for patients with lymphatic abnormalities.Jason T. BoehmeCatherine J. MorrisSamuel R. ChiacchiaWenhui GongKatherine Y. WuRebecca J. KamenyGary W. RaffJeffrey R. FinemanEmin MaltepeSanjeev A. DatarNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-14 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Jason T. Boehme Catherine J. Morris Samuel R. Chiacchia Wenhui Gong Katherine Y. Wu Rebecca J. Kameny Gary W. Raff Jeffrey R. Fineman Emin Maltepe Sanjeev A. Datar HIF-1α promotes cellular growth in lymphatic endothelial cells exposed to chronically elevated pulmonary lymph flow
description	Abstract Normal growth and development of lymphatic structures depends on mechanical forces created by accumulating interstitial fluid. However, prolonged exposure to pathologic mechanical stimuli generated by chronically elevated lymph flow results in lymphatic dysfunction. The mechanisms that transduce these mechanical forces are not fully understood. Our objective was to investigate molecular mechanisms that alter the growth and metabolism of isolated lymphatic endothelial cells (LECs) exposed to prolonged pathologically elevated lymph flow in vivo within the anatomic and physiologic context of a large animal model of congenital heart disease with increased pulmonary blood flow using in vitro approaches. To this end, late gestation fetal lambs underwent in utero placement of an aortopulmonary graft (shunt). Four weeks after birth, LECs were isolated and cultured from control and shunt lambs. Redox status and proliferation were quantified, and transcriptional profiling and metabolomic analyses were performed. Shunt LECs exhibited hyperproliferative growth driven by increased levels of Hypoxia Inducible Factor 1α (HIF-1α), along with upregulated expression of known HIF-1α target genes in response to mechanical stimuli and shear stress. Compared to control LECs, shunt LECs exhibited abnormal metabolism including abnormalities of glycolysis, the TCA cycle and aerobic respiration. In conclusion, LECs from lambs exposed in vivo to chronically increased pulmonary lymph flow are hyperproliferative, have enhanced expression of HIF-1α and its target genes, and demonstrate altered central carbon metabolism in vitro. Importantly, these findings suggest provocative therapeutic targets for patients with lymphatic abnormalities.
format	article
author	Jason T. Boehme Catherine J. Morris Samuel R. Chiacchia Wenhui Gong Katherine Y. Wu Rebecca J. Kameny Gary W. Raff Jeffrey R. Fineman Emin Maltepe Sanjeev A. Datar
author_facet	Jason T. Boehme Catherine J. Morris Samuel R. Chiacchia Wenhui Gong Katherine Y. Wu Rebecca J. Kameny Gary W. Raff Jeffrey R. Fineman Emin Maltepe Sanjeev A. Datar
author_sort	Jason T. Boehme
title	HIF-1α promotes cellular growth in lymphatic endothelial cells exposed to chronically elevated pulmonary lymph flow
title_short	HIF-1α promotes cellular growth in lymphatic endothelial cells exposed to chronically elevated pulmonary lymph flow
title_full	HIF-1α promotes cellular growth in lymphatic endothelial cells exposed to chronically elevated pulmonary lymph flow
title_fullStr	HIF-1α promotes cellular growth in lymphatic endothelial cells exposed to chronically elevated pulmonary lymph flow
title_full_unstemmed	HIF-1α promotes cellular growth in lymphatic endothelial cells exposed to chronically elevated pulmonary lymph flow
title_sort	hif-1α promotes cellular growth in lymphatic endothelial cells exposed to chronically elevated pulmonary lymph flow
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/21ad722718874b2cb2712a1a9ed64d7b
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HIF-1α promotes cellular growth in lymphatic endothelial cells exposed to chronically elevated pulmonary lymph flow

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