Surface Density of Vascular Endothelial Growth Factor Modulates Endothelial Proliferation and Differentiation

Abstract

Therapeutic strategies aim to regulate vasculature either by encouraging vessel growth for tissue engineering or inhibiting vascularization around a tumor. Vascular endothelial growth factor (VEGF) is essential to these processes, and there are several strategies that manipulate VEGF signaling. Here we develop a method to control the surface density of VEGF, which is covalently attached to tissue culture polystyrene (TCPS), and explore cellular responses to surfaces with varying VEGF densities. We show that the crosslinker reduces but does not eliminate the biological activity of soluble VEGF as measured by endothelial proliferation. However, endothelial cells cultured on surfaces of covalently bound VEGF did not proliferate in response to surface cues. Interestingly, compared to cells incubated with soluble VEGF (10 ng/ml) and cultured on TCPS, lower cell proliferation was observed when endothelial cells were cultured on high VEGF surface densities (5.9 ng/cm(2)), whereas higher cell proliferation occurred when cells were cultured on low surface densities (0.04 ng/cm(2)). High density surfaces (5.9 ng/cm(2)) also acted in synergy with an inhibitor of VEGF receptors to further suppress endothelial cell proliferation. We also examined the effect of VEGF surfaces on endothelial differentiation of mesenchymal stem cells. No effect was observed when cells were cultured on VEGF surfaces; however, the VEGF surfaces acted in synergy with an inhibitor of VEGF receptors to decrease the ability of differentiated cells to form vascular networks. Together, these results suggest that surface density of bound VEGF can be used to modulate cell behavior and inhibit an angiogenic response.

Role and regulation of growth plate vascularization during coupling with osteogenesis in tibial dyschondroplasia of chickens

“…4a ). VEGF and its receptors (including VEGFR1 and VEGFR2) not only have an effect on the vascular differentiation but also play a key role in vascular proliferation 16 – 18 . qRT-PCR further confirmed that the levels of the VEGFA and its receptors in proximal TGPs were significantly lower in TD chickens at 7 days old, which markedly recovered at 10 and 14 days of age due to the removal of thiram compared with the levels in the normal group (Fig.…”

“…Among these, vasculogenesis refers to the de novo emergence of a vascular network to initiate the formation of blood islands from mesodermal progenitors to hemangioblasts, followed by migration and association of endothelial cells to form a primitive capillary plexus 14 , 15 , whereas angiogenesis refers to the generation of vessels by sprouting or non-sprouting from pre-existing capillaries 12 . In this process, a variety of angiogenic factors, including vascular endothelial growth factor (VEGF) and its receptors 16 – 18 , the fibroblast growth factor (FGF) family 19 , platelet-derived growth factor (PDGF)-BB and its receptor 20 , 21 , angiopoietin-1 (Ang1), Ang2 and their endothelium-specific receptors such as tyrosine kinase Tie2 (also known as Tek) 22 , 23 , are all widely expressed as primary inducers of vascular development and postnatal angiogenesis 24 , 25 . Among these, blockage of the VEGF receptors VEGFR1 and VEGFR2 contributes to decreased blood vessel formation and bone regeneration 17 .…”

Nanotubular TiO₂ regulates macrophage M2 polarization and increases macrophage secretion of VEGF to accelerate endothelialization via the ERK1/2 and PI3K/AKT pathways

“…20,21 M2 macrophages produce arginase-1 (ARG1), mannose receptor (CD206), and IL-10 22 as well as vascular endothelial growth factor (VEGF), 23,24 which supports the homing, migration, and proliferation of endothelial cells. 25 Therefore, further studies are needed to investigate the promotion/inhibition of HUVEC behaviors by the mixture secreted by macrophages on the surface of TiO 2 nanotubes. Accordingly, in this study, we evaluated the inflammatory response to commercially pure Ti (CP) and to TiO 2 nanotubes generated using 20 (TNT20), 40 (TNT40), and 60 V (TNT60).…”

Controlled co-immobilization of EGF and VEGF to optimize vascular cell survival

“…[4][5][6] Such GF-modified biomaterials have been shown to promote in vitro cell proliferation, [7,8] migration [8,9] and differentiation. [10,11] However, most of the studies on the biological modification of materials rely on the addition of a single GF, while in their physiological environment, GFs are often combined, and complex processes such as wound healing or angiogenesis typically involve several signalling proteins possessing synergistic or complementary actions. [12][13][14][15] This generated a growing interest in biomimetic materials delivering or displaying multiple GFs.…”