Life is a pattern: vascular assembly within the embryo

Abstract

The formation of the vascular system is one of the earliest and most important events during organogenesis in the developing embryo because the growing organism needs a transportation system to supply oxygen and nutrients and to remove waste products. Two distinct processes termed vasculogenesis and angiogenesis lead to a complex vasculature covering the entire body. Several cellular mechanisms including migration, proliferation, differentiation and maturation are involved in generating this hierarchical vascular tree. To achieve this aim, a multitude of signaling pathways need to be activated and coordinated in spatio-temporal patterns. Understanding embryonic molecular mechanism in angiogenesis further provides insight for therapeutic approaches in pathological conditions like cancer or ischemic diseases in the adult. In this review, we describe the current understanding of major signaling pathways that are necessary and active during vascular development.

Figure 1

Schematic overview of vasculogenesis and angiogenesis. During development, mesodermal cells differentiate into haemangioblasts, which further develop into angioblast, the precursors of endothelial cells. Vasculogenesis involves the differentiation of endothelial cells (ECs) from these angioblast cells to form a primitive vascular plexus. Remodeling and growing processes of these pre-existing vessels is termed angiogenesis. Intussusceptive angiogenesis involves splitting by the formation of translumen pillars and growing of vessels. In sprouting angiogenesis, endothelial cells proliferate behind the tip cell of a growing branch in response to cytokines and lumens can form by vacuole fusion. Both forms of angiogenesis require the recruitment of smooth muscle cells (SMCs) or pericytes to stabilize the nascent vessels. Neighboring mesenchymal cells migrate towards the neovessel in response to platelet-derived growth factor (PDGF), which then differentiate into vascular SMCs (vSMCs) in response to transforming growth factor-beta (TGF-b) signaling.

Figure 2

Arterial-venous and lymphatic specification in vertebrate embryo. Due to secretion of sonic hedgehog from the notochord VEGF expression is induced in adjacent somites. In nearby ECs VEGF leads to FoxC1 and FoxC2 mediated upregulation of components of the Notch signalling pathway (Notch-1 and DLL4). Thereupon Hey1/2 are expressed which, in addition to Sox7, Sox17 and Sox18, lead to arterial specification and EphrinB2 marker expression. COUP-TFII is responsible for suppression of Nrp1 expression and inhibits Notch signalling which leads to venous differentiation with the marker expression of Nrp2 and EphB4. Later on some venous ECs of the anterior cardinal vein begin to express Sox18 that precedes expression of Prox-1 and COUP-TFII. Prox-1 induces expression of lymphatic markers like podoplanin and is the major mediator for LECs specification. Modified from (175).