Blood flow reprograms lymphatic vessels to blood vessels
Chiu-Yu Chen, … , Guillermo Oliver, Mark L. Kahn
Chiu-Yu Chen, … , Guillermo Oliver, Mark L. Kahn
Published May 24, 2012
Citation Information: J Clin Invest. 2012;122(6):2006-2017. https://doi.org/10.1172/JCI57513.
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Research Article Vascular biology

Blood flow reprograms lymphatic vessels to blood vessels

Abstract

Human vascular malformations cause disease as a result of changes in blood flow and vascular hemodynamic forces. Although the genetic mutations that underlie the formation of many human vascular malformations are known, the extent to which abnormal blood flow can subsequently influence the vascular genetic program and natural history is not. Loss of the SH2 domain–containing leukocyte protein of 76 kDa (SLP76) resulted in a vascular malformation that directed blood flow through mesenteric lymphatic vessels after birth in mice. Mesenteric vessels in the position of the congenital lymphatic in mature Slp76-null mice lacked lymphatic identity and expressed a marker of blood vessel identity. Genetic lineage tracing demonstrated that this change in vessel identity was the result of lymphatic endothelial cell reprogramming rather than replacement by blood endothelial cells. Exposure of lymphatic vessels to blood in the absence of significant flow did not alter vessel identity in vivo, but lymphatic endothelial cells exposed to similar levels of shear stress ex vivo rapidly lost expression of PROX1, a lymphatic fate–specifying transcription factor. These findings reveal that blood flow can convert lymphatic vessels to blood vessels, demonstrating that hemodynamic forces may reprogram endothelial and vessel identity in cardiovascular diseases associated with abnormal flow.

Authors

Chiu-Yu Chen, Cara Bertozzi, Zhiying Zou, Lijun Yuan, John S. Lee, MinMin Lu, Stan J. Stachelek, Sathish Srinivasan, Lili Guo, Andres Vincente, Patricia Mericko, Robert J. Levy, Taija Makinen, Guillermo Oliver, Mark L. Kahn

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Figure 1

Late separation of the blood and lymphatic circulations in SLP76-deficient mice.

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Late separation of the blood and lymphatic circulations in SLP76-deficie...
(A) Cutaneous edema resolves in Slp76–/– embryos between E15 and E18. Arrows indicate sites of raised skin indicative of edema at E15 (top) and the presence of normal skin folds indicating a lack of edema at E18 (bottom). (B) Blood-filled lymphatics resolve in the skin of Slp76–/– embryos at the same time that they appear in the intestine. LYVE1 staining (brown) identifies lymphatic vessels in the skin and intestine of E15 and neonatal Slp76–/– animals. Arrows indicate blood-filled lymphatics in E15 skin and in neonatal intestine. (C) Functional identification of blood-filled lymphatics in neonatal Slp76–/– animals using intravenous injection of biotinylated lectin. Blood-perfused vessels are identified by FITC-streptavidin binding to biotin-lectin after intravenous injection (green), and lymphatic vessels are visualized by LYVE1 immunostaining (red). Co-stained vessels are present in the intestine and mesentery but not skin of Slp76–/– neonates (arrows). (D) Late resolution of mesenteric and intestinal blood-lymphatic mixing in Slp76–/– mice demonstrated using staining for injected biotin-lectin and LYVE1. Scale bars: 50 μm.