Mechanisms of new blood-vessel formation and proliferative heterogeneity of endothelial cells

Abstract

The vast blood-vessel network of the circulatory system is crucial for maintaining bodily homeostasis, delivering essential molecules and blood cells, and removing waste products. Blood-vessel dysfunction and dysregulation of new blood-vessel formation are related to the onset and progression of many diseases including cancer, ischemic disease, inflammation and immune disorders. Endothelial cells (ECs) are fundamental components of blood vessels and their proliferation is essential for new vessel formation, making them good therapeutic targets for regulating the latter. New blood-vessel formation occurs by vasculogenesis and angiogenesis during development. Induction of ECs termed tip, stalk and phalanx cells by interactions between vascular endothelial growth factor A (VEGF-A) and its receptors (VEGFR1–3) and between Notch and Delta-like Notch ligands (DLLs) is crucial for regulation of angiogenesis. Although the importance of angiogenesis is unequivocal in the adult, vasculogenesis effected by endothelial progenitor cells (EPCs) may also contribute to post-natal vessel formation. However, the definition of these cells is ambiguous and they include several distinct cell types under the simple classification of ‘EPC’. Furthermore, recent evidence indicates that ECs within the intima show clonal expansion in some situations and that they may harbor vascular-resident endothelial stem cells. In this article, we summarize recent knowledge on vascular development and new blood-vessel formation in the adult. We also introduce concepts of EC heterogeneity and EC clonal expansion, referring to our own recent findings.

BMP9 exhibits dual and coupled roles in inducing osteogenic and angiogenic differentiation of mesenchymal stem cells

“…In this stage, VEGFR2, or KDR, is the earliest and specific marker. Fibroblast growth factor 2 (FGF2) and BMP4 were reported to initiate the specification of the mesoderm and differentiation toward ECs [48]. In the present study, we found that BMP9 up-regulates the expression of KDR at the early stage of osteogenesis in the ectopic bone formation model, which indicates that BMP9 could trigger the process of vasculogenesis.…”

“…Recently, the blood vessel formation process was identified as two stages [48][49][50]. The first stage is vasculogenesis, when mesodermal precursor cells undergo angioblasts differentiation toward ECs.…”

Endothelial TRPV1 as an Emerging Molecular Target to Promote Therapeutic Angiogenesis

“…Embryonal vasculogenesis represents one of the earliest events during organogenesis, as it starts already during gastrulation [50,51]. Vasculogenesis consists in the differentiation, expansion, and assembly of endothelial precursors into a functional blood vessel [49,52]. Vascular development in the embryo is initiated by mesodermal cells, also referred to as hemangioblasts, which migrate into the yolk sac, to form cellular aggregates known as blood islands.…”

When Innate Immunity Meets Angiogenesis—The Role of Toll-Like Receptors in Endothelial Cells and Pulmonary Hypertension

“…The network of blood vessels expands via two main mechanisms: vasculogenesis is de novo formation of blood vessels, and angiogenesis is sprouting or splitting of existing blood vessels (83). Sprouting angiogenesis occurs in five steps: (A) After action of angiogenic growth factor (e.g., vascular endothelial growth factor, VEGF) on a quiescent blood vessel, there is (B) degradation of the capillary basement membrane followed by (C) EC proliferation and (D) selection of tip and stalk cells.…”