Abstract
Endothelial cells throughout the body are heterogeneous, and this is tightly linked to the specific functions of organs and tissues. Heterogeneity is already determined from development onwards and ranges from arterial/venous specification to microvascular fate determination in organ-specific differentiation. Acknowledging the different phenotypes of endothelial cells and the implications of this diversity is key for the development of more specialized tissue engineering and vascular repair approaches. However, although novel technologies in transcriptomics and proteomics are facilitating the unraveling of vascular bed-specific endothelial cell signatures, still much research is based on the use of insufficiently specialized endothelial cells. Endothelial cells are not only heterogeneous, but their specialized phenotypes are also dynamic and adapt to changes in their microenvironment. During the last decades, strong collaborations between molecular biology, mechanobiology, and computational disciplines have led to a better understanding of how endothelial cells are modulated by their mechanical and biochemical contexts. Yet, because of the use of insufficiently specialized endothelial cells, there is still a huge lack of knowledge in how tissue-specific biomechanical factors determine organ-specific phenotypes. With this review, we want to put the focus on how organ-specific endothelial cell signatures are determined from development onwards and conditioned by their microenvironments during adulthood. We discuss the latest research performed on endothelial cells, pointing out the important implications of mimicking tissue-specific biomechanical cues in culture.
Highlights
This brings us to the second common limitation: after few passages, organ-specific endothelial cells lose many of their specific features if they do not meet their microenvironmental requirements
Collagen type IV and Fibronectin are secreted by human umbilical artery endothelial cells (HUAECs) and human umbilical vein endothelial cells (HUVECs) under both physiological (5% O2 ) and hypoxic (1% O2 ) conditions, whereas collagen type I is only deposited under physiological O2 levels [140]
New transcriptomic and proteomic insights are being revealed for the characterization of these bed-specific endothelial cells
Summary
Endothelial cells have a mesodermal origin; during vasculogenesis, a “first draft”. of the vascular system is laid down to support the growing embryo [10]. VEGF signaling is abundantly studied as a critical mediator of vasculogenesis [13,14,15,16] Both heterozygous and homozygous Vegf-A null mice died during embryonic development, at E11.5 and E9.5, respectively, due to impaired angiogenesis and disrupted formation of the blood islands [13,14]. VEGF signaling drives endothelial development, its own expression is regulated by the microenvironment of the developing tissue. FGF10 drives mTORC1/Sprouty signaling in epithelial cells, which initiates the production of VEGF by the epithelium [23]. In the developing heart, cardiomyocytes are an important source of VEGF for the coronary vessels; embryos with a cardiomyocyte-specific Vegf ablation present with fewer coronary vessels and a thinned ventricular wall at E13.5, suggesting that the tissue-specific microenvironment regulates endothelial differentiation by regulating VEGF expression [25]. During development and throughout adult life, new blood vessels are created from the existing vasculature during either sprouting angiogenesis or intussusceptive angiogenesis [31]
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