Lymphatic vessel development: fluid flow and valve-forming cells

Abstract

Hemodynamic forces regulate many aspects of blood vessel disease and development, including susceptibility to atherosclerosis and remodeling of primary blood vessels into a mature vascular network. Vessels of the lymphatic circulatory system are also subjected to fluid flow-associated forces, but the molecular and cellular mechanisms by which these forces regulate the formation and maintenance of lymphatic vessels remain largely uncharacterized. This issue of the JCI includes two articles that begin to address how fluid flow influences lymphatic vessel development and function. Sweet et al. demonstrate that lymph flow is essential for the remodeling of primary lymphatic vessels, for ensuring the proper distribution of smooth muscle cells (SMCs), and for the development and maturation of lymphatic valves. Kazenwadel et al. show that flow-induced lymphatic valve development is initiated by the upregulation of GATA2, which has been linked to lymphedema in patients with Emberger syndrome. Together, these observations and future studies inspired by these results have potential to lead to the development of strategies for the treatment of lymphatic disorders.

Figure 1. Mechanism of flow-dependent lymphatic vessel remodeling and valve formation in the developing mesentery.

(A) Sites of vessel bifurcation in the primary lymphatic plexus produce turbulence in the flow of lymph (dashed arrow), which leads to an increase in the expression of GATA2. GATA2 is an upstream component of the mechanism by which the expression of FOXC2 and PROX1 in valve-forming cells establishes the site of valve formation. The studies by Kazenwadel et al. and Sweet et al. demonstrate that GATA2 is upregulated in response to shear stress and suggest that GATA2 binding at enhancer elements adjacent to PROX1- and FOXC2-encoding loci promotes expression of these known regulators of lymphatic development (inset). (B) Lymph flow (arrow) is also essential for lymphatic vessel remodeling and for proper recruitment of vascular SMCs (purple) to lymphatic collecting vessels.