Regulation of VEGFR Signalling in Lymphatic Vascular Development and Disease: An Update.

Genevieve A Secker,Natasha L Harvey

doi:10.3390/ijms22147760

Abstract

The importance of lymphatic vessels in a myriad of human diseases is rapidly gaining recognition; lymphatic vessel dysfunction is a feature of disorders including congenital lymphatic anomalies, primary lymphoedema and obesity, while improved lymphatic vessel function increases the efficacy of immunotherapy for cancer and neurological disease and promotes cardiac repair following myocardial infarction. Understanding how the growth and function of lymphatic vessels is precisely regulated therefore stands to inform the development of novel therapeutics applicable to a wide range of human diseases. Lymphatic vascular development is initiated during embryogenesis following establishment of the major blood vessels and the onset of blood flow. Lymphatic endothelial progenitor cells arise from a combination of venous and non-venous sources to generate the initial lymphatic vascular structures in the vertebrate embryo, which are then further ramified and remodelled to elaborate an extensive lymphatic vascular network. Signalling mediated via vascular endothelial growth factor (VEGF) family members and vascular endothelial growth factor receptor (VEGFR) tyrosine kinases is crucial for development of both the blood and lymphatic vascular networks, though distinct components are utilised to different degrees in each vascular compartment. Although much is known about the regulation of VEGFA/VEGFR2 signalling in the blood vasculature, less is understood regarding the mechanisms by which VEGFC/VEGFD/VEGFR3 signalling is regulated during lymphatic vascular development. This review will focus on recent advances in our understanding of the cellular and molecular mechanisms regulating VEGFA-, VEGFC- and VEGFD-mediated signalling via VEGFRs which are important for driving the construction of lymphatic vessels during development and disease.

Highlights

While early studies suggested that, once established, the lymphatic vessels of most tissues in postnatal and adult mice are refractory to VEGFC and VEGFD blockade [39], recent work employing conditional deletion of Vegfc, and inducible expression of soluble VEGFR3, revealed that selected lymphatic beds including the intestinal lacteals and meningeal lymphatic vessels remain dependent on, or sensitive to, VEGFC/VEGFR3 signalling during adulthood [40,41]
This study found that VEGFR3 phosphorylation was decreased in Sdn4 deficient cells exposed to flow, and that attributed the defects in lymphatic endothelial cell polarity to elevated levels of the planar cell polarity protein
The identification of new proteases that proteolytically activate VEGFC and VEGFD, together with their cellular sources and matrix components responsible for regulating ligand cleavage and/or retention, have vastly improved our understanding of the mechanisms regulating patterning of the lymphatic vasculature during development. It will be intriguing in future work to investigate how similar, or distinct, the factors regulating lymphatic patterning are across different tissues and in settings of pathology

Summary

Introduction

Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. Collecting lymphatic vessels are sub-divided into segments called lymphangions, punctuated by semi-lunar valves important for unidirectional lymph flow, and are invested with lymphatic muscle cells. Recent work in which Flt was selectively deleted in the lymphatic vasculature at the onset of lymphatic vascular development in the mouse embryo confirmed the crucial role of VEGFR3 in lymphatic endothelial cell sprouting and migration, demonstrating that. While early studies suggested that, once established, the lymphatic vessels of most tissues in postnatal and adult mice are refractory to VEGFC and VEGFD blockade [39], recent work employing conditional deletion of Vegfc, and inducible expression of soluble VEGFR3, revealed that selected lymphatic beds including the intestinal lacteals and meningeal lymphatic vessels remain dependent on, or sensitive to, VEGFC/VEGFR3 signalling during adulthood [40,41]

The Vascular Endothelial Growth Factor Family

Vascular Endothelial Growth Factor Receptors and Co-Receptors

VEGFR Signal Transduction in Lymphatic Endothelial Cells

Regulation of VEGFR Signalling in the Lymphatic Vasculature

Mechanical Regulation of VEGFR Signalling during Lymphatic

Conclusions and Future Directions