Adrenomedullin signaling is necessary for murine lymphatic vascular development.

Adrenomedullin signaling is necessary for murine lymphatic vascular development. Research Abstract Details 

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Adrenomedullin signaling is necessary for murine lymphatic vascular development. Abstract Text:

Kimberly L Fritz-Six,William P Dunworth,Manyu Li,Kathleen M Caron,Kimberly L Fritz-Six,William P Dunworth,Manyu Li,Kathleen M Caron,

The lymphatic vascular system mediates fluid homeostasis, immune defense, and tumor metastasis. Only a handful of genes are known to affect the development of the lymphatic vasculature, and even fewer represent therapeutic targets for lymphatic diseases. Adrenomedullin (AM) is a multifunctional peptide vasodilator that transduces its effects through the calcitonin receptor-like receptor (calcrl) when the receptor is associated with a receptor activity-modifying protein (RAMP2). Here we report on the involvement of these genes in lymphangiogenesis. AM-, calcrl-, or RAMP2-null mice died mid-gestation after development of interstitial lymphedema. This conserved phenotype provided in vivo evidence that these components were required for AM signaling during embryogenesis. A conditional knockout line with loss of calcrl in endothelial cells confirmed an essential role for AM signaling in vascular development. Loss of AM signaling resulted in abnormal jugular lymphatic vessels due to reduction in lymphatic endothelial cell proliferation. Furthermore, AM caused enhanced activation of ERK signaling in human lymphatic versus blood endothelial cells, likely due to induction of CALCRL gene expression by the lymphatic transcriptional regulator Prox1. Collectively, our studies identify a class of genes involved in lymphangiogenesis that represent a pharmacologically tractable system for the treatment of lymphedema or inhibition of tumor metastasis.

Adrenomedullin signaling is necessary for murine lymphatic vascular development. Publishing Authors By Initials

KL Fritz-Six,WP Dunworth,M Li,KM Caron,KL Fritz-Six,WP Dunworth,M Li,KM Caron,

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Adrenomedullin signaling is necessary for murine lymphatic vascular development. Journal Published:

PUBLICATION TYPE: Journal Article

Journal: The Journal of clinical investigation

VOLUME: 118

Page Numbers: 40-50

Journal Abbreviation: J. Clin. Invest.

ISSN: 0021-9738

DAY: 3

MONTH: Jan

YEAR: 2008

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LANGUAGE: eng

NlmUniqueID: 7802877

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Grant and Affiliation Information for Adrenomedullin signaling is necessary for murine lymphatic vascular development.

AFFILIATION: Department of Cell and Molecular Physiology and Department of Genetics, The University of North Carolina, Chapel Hill, North Carolina, USA.

Country: United States

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MEDLINETA: J Clin Invest

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