Role of the Endothelium in Neonatal Diseases

Abstract

In both fetal and neonatal physiologic and pathologic processes in most organs, endothelial cells are known to play critical roles. Although the endothelium is one of the most ubiquitous cell type in the body, the tight adherence to the blood vessel wall has made it difficult to study their diverse function and structure. In this article, we have reviewed endothelial cell origins and explored their heterogeneity in terms of structure, function, developmental changes, and their role in inflammatory and infectious diseases. We have also attempted to evaluate the untapped therapeutic potentials of endothelial cells in neonatal disease. This article comprises various peer-reviewed studies, including ours, and an extensive database literature search from EMBASE, PubMed, and Scopus.

Keywords: Angiogenesis; Bronchopulmonary dysplasia; Endothelium; Necrotizing enterocolitis; Neonate; Retinopathy of prematurity.

Fig. 1:

Origin of endothelial cells. Overall schematic of the common origin of endothelial progenitor cells and the erythroid, lymphoid, myeloid precursors. Hematopoietic and endothelial progenitor cells are derived from a common precursor, the hemangioblast. Embryonic stem cells give rise to neural crest cells, mesoderm, and hemangioblasts. Hemangioblasts are derived from the yolk sac endothelium. Neural crest cells differentiate into mesenchymal stem cells, which tissue-resident precursors through chondro-, osteo- and adipogenesis. Endothelial precursors can arise from the yolk sac, myeloid precursors, and hemangioblasts

Fig. 2:

Differentiation of endothelial progenitor cells. Hemangioblasts differentiate into hematopoietic stem cells and endothelial progenitor cells. Hematopoietic stem cells and endothelial progenitor cells express three markers cluster of differentiation (CD) 34, CD 45, CD133, and vascular endothelial growth factor receptor-2 (VEGFR2). CD133 is a marker for immature hematopoietic stem cell, while CD34 is a classic hematopoietic stem cell marker. Hematopoietic stem cells give rise to myeloid cell lineage, which express CD14 and CD45, and are CD133 negative, which ultimately give rise to monocytes and macrophages. As endothelial progenitor cells differentiate, they lose CD133 and begin to express CD31, CD144, vascular endothelial cadherin, VEGFR2, endothelial nitric oxide synthase (eNOS), and von Willebrand factor (vWF). Endothelial progenitor cells are positive for both hematopoietic stem cell marker CD34 or CD133 and an endothelial marker, such as VEGFR2. Endothelial progenitor cells do not have exclusive surface markers, rather share similar markers with mature endothelial cells

Fig. 3:

Endothelial markers in inflammation and angiogenesis. VEGF works together with angiopoietins during inflammation and angiogenesis, and both have receptors on endothelial cells. Ang-1 and -2 bind to their receptors Tie 2. Ang-1–Tie 2 signaling contributes to maintaining a quiescent endothelial cell phenotype. Ang-1 is pro-angiogenic and required for vascular remodeling, while Ang-2 counteracts their effects as anti-angiogenic. VEGF has two transmembrane receptors, Flt1 or VEGFR1 and Flk-1 or VEGFR2. VEGFR1 has two forms generated by alternative splicing, a membrane-bound Flt1 and a soluble Flt1 receptor, VEGF signals through VEGFR2 to promote angiogenesis. VEGFR1 (Flt-1) serves to limit the actions of (VEGFR2) Flk-1. Ang-2 binds to Tie 2 to activate P13-K/Akt signaling. VEGF-VEGFR2 activates MAPK/AKT signaling pathways