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 6

Fluid shear forces equivalent to those in Slp76–/– mesenteric lymphatics drive loss of PROX1 expression in LECs.

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Fluid shear forces equivalent to those in Slp76–/– mesenteric lymphatics...
(A) Representative mesenteric vessels in 12-week-old Slp76+/+ and Slp76–/– animals that were studied using Doppler ultrasound. The dilated, blood-containing vein and congenital lymphatic are denoted as SV1 and SV2. (B) The vessels shown in A were visualized using 2D ultrasound. (C and D) The pulsed-wave Doppler signals and measured flow velocity of blood in the vessels indicated in A and B are shown. Note the difference in direction of flow between the arteries and veins or efferent SVs. (E) Calculated shear stresses for Slp76+/+ veins and Slp76–/– SVs. Slp76–/– data points in the same color indicate values of paired SVs from the same mesenteric bundle. (F) LECs exposed to flow downregulate PROX1. LECs were subjected to a shear stress of 20 dynes/cm2 for 8 hours, and the expression of the indicated mRNAs measured using qPCR. n = 7. **P < 0.01. (G) Loss of PROX1 protein in LECs exposed to shear. Anti-PROX1 immunostaining in primary LECs is shown compared with DAPI staining of cell nuclei. (H) Shear-mediated downregulation of PROX1 is transient in cultured endothelial cells. PROX1 levels were measured after 8 hours of static culture, 8 hours of flow, or 8 hours of flow followed by 24 hours of static culture. *P < 0.05, **P < 0.01. Scale bars: 25 μm.