Computational Modeling to Quantify the Contributions of VEGFR1, VEGFR2, and Lateral Inhibition in Sprouting Angiogenesis.

Clemens Kühn,Sara Checa

doi:10.3389/fphys.2019.00288

Abstract

Sprouting angiogenesis is a necessary process in regeneration and development as well as in tumorigenesis. VEGF-A is the main pro-angiogenic chemoattractant and it can bind to the decoy receptor VEGFR1 or to VEGFR2 to induce sprouting. Active sprout cells express Dll4, which binds to Notch1 on neighboring cells, in turn inhibiting VEGFR2 expression. It is known that the balance between VEGFR2 and VEGFR1 determines tip selection and network architecture, however the quantitative interrelationship of the receptors and their interrelated balances, also with relation to Dll4-Notch1 signaling, remains yet largely unknown. Here, we present an agent-based computer model of sprouting angiogenesis, integrating VEGFR1 and VEGFR2 in a detailed model of cellular signaling. Our model reproduces experimental data on VEGFR1 knockout. We show that soluble VEGFR1 improves the efficiency of angiogenesis by directing sprouts away from existing cells over a wide range of parameters. Our analysis unravels the relevance of the stability of the active notch intracellular domain as a dominating hub in this regulatory network. Our analysis quantitatively dissects the regulatory interactions in sprouting angiogenesis. Because we use a detailed model of intracellular signaling, the results of our analysis are directly linked to biological entities. We provide our computational model and simulation engine for integration in complementary modeling approaches.

Highlights

Angiogenesis is a pivotal process in various aspects of vertebrate life
Our analysis shows that VEGFR1 is efficient in guiding sprouts away from existing vessels and it highlights the importance of Delta-Notch signaling, the degradation of notch intracellular domain (NICD), for angiogenesis
We present an agent based computer model of sprouting angiogenesis focusing on intracellular signaling and its effects on pattern formation

Summary

Introduction

Angiogenesis is a pivotal process in various aspects of vertebrate life. In development (Breier, 2000) as well as in regenerative processes like wound healing (Flegg et al, 2015) and bone fracture healing (Checa and Prendergast, 2009; Carlier et al, 2015a), angiogenesis is necessary to support newly forming tissue with oxygen and nutrients. Tumors abuse sprouting angiogenesis to direct vascularization toward them (MacGabhann and Popel, 2006). A quantitative understanding of the molecular mechanisms that shape vascular network structure can lead to improved treatment options in regenerative medicine and beyond, such as in oncology. Quiescent endothelial cells (ECs) in an existing vessel adopt a motile tip cell phenotype, release matrix metalloproteases (MMPs) to degrade the extracellular matrix (ECM) around the vessel, and lead a sprout followed by proliferative stalk cells (Logsdon et al, 2014). The sprouts extend to neighboring vessels and undergo anastomosis and

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Conclusion