Cellular and molecular mechanisms of vascular lumen formation

Abstract

The formation of vascular lumens by endothelial cells is a critical step in the angiogenic process that occurs during invasion and growth of the incipient vascular sprout. Once a lumen is established, capillaries are rapidly exposed to the physical forces associated with the flow of blood which, together with genetic information, regulate the ultimate size of inner vessel diameter. Here we review the recent literature on vascular lumen formation and compare it to lumen formation in other epithelial systems. We also discuss the regulation of lumen diameter after vascular morphogenesis has been completed.

Figure 1.. Cellular and Molecular Regulation of Vascular Lumen Formation

The morphogenesis of lumens in ECs occurs concomitantly with the invasion of vascular sprouts. Either as single or multiple cellular aggregates, the first cellular indication of lumen formation is the presence of large intracellular vesicles (left panel). Upon fusion, the vesicles form an incipient lumen (central panel) that aligns with the patent circulation. Molecular requirements for these events include the activity of integrins, Cdc42 and Rac, in addition to Pak2, Pak4, and the polarity complex Par3/Par6/PKCζ. The activity of proteinases, in particular MT1-MMP, is also required.

Figure 2.. Genetic Determinants of Vascular Lumen Size

(A) Gain- and loss-of-function studies in mice have indicated that Notch regulates the diameter of vascular lumens. Specifically, loss-of-function analysis of Notch1 null E9.5 mouse embryos showed narrow vascular tubes. In contrast, overexpression of an activated form of Notch results in significant vascular lumen expansion. The diagram illustrates a transverse section of mouse embryos at E9.5 to indicate the relative differences between wild-type, loss of Notch 1 expression, and gain of Notch 1 expression. NT, neural tube. (B) Genetic studies with exclusive expression of specific VEGF isoforms, as well as tumor studies, have indicated that matrix-bound and soluble VEGF mediates distinct modes of vascular expansion in a manner that affects the lumenal compartment. Thus, soluble VEGF (right panel) mediates expansion of existent vessels, resulting in enlarged, hyperplastic structures. In contrast, matrix-bound VEGF elicits rapid capillary sprouts and results in increased vascular density (middle panel) in comparison with wild-type control (left panel).