Numerical evaluation reveals the effect of branching morphology on vessel transport properties during angiogenesis

PLoS Comput Biol. 2021 Jun 16;17(6):e1008398. doi: 10.1371/journal.pcbi.1008398. eCollection 2021 Jun.

Abstract

Blood flow governs transport of oxygen and nutrients into tissues. Hypoxic tissues secrete VEGFs to promote angiogenesis during development and in tissue homeostasis. In contrast, tumors enhance pathologic angiogenesis during growth and metastasis, suggesting suppression of tumor angiogenesis could limit tumor growth. In line with these observations, various factors have been identified to control vessel formation in the last decades. However, their impacts on the vascular transport properties of oxygen remain elusive. Here, we take a computational approach to examine the effects of vascular branching on blood flow in the growing vasculature. First of all, we reconstruct a 3D vascular model from the 2D confocal images of the growing vasculature at postnatal day 5 (P5) mouse retina, then simulate blood flow in the vasculatures, which are obtained from the gene targeting mouse models causing hypo- or hyper-branching vascular formation. Interestingly, hyper-branching morphology attenuates effective blood flow at the angiogenic front, likely promoting tissue hypoxia. In contrast, vascular hypo-branching enhances blood supply at the angiogenic front of the growing vasculature. Oxygen supply by newly formed blood vessels improves local hypoxia and decreases VEGF expression at the angiogenic front during angiogenesis. Consistent with the simulation results indicating improved blood flow in the hypo-branching vasculature, VEGF expression around the angiogenic front is reduced in those mouse retinas. Conversely, VEGF expression is enhanced in the angiogenic front of hyper-branching vasculature. Our results indicate the importance of detailed flow analysis in evaluating the vascular transport properties of branching morphology of the blood vessels.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Mice
  • Mice, Transgenic
  • Neovascularization, Pathologic*
  • Retinal Vessels / anatomy & histology
  • Retinal Vessels / metabolism
  • Retinal Vessels / physiopathology*
  • Vascular Endothelial Growth Factor A / metabolism

Substances

  • Vascular Endothelial Growth Factor A
  • vascular endothelial growth factor A, mouse

Grants and funding

Funding for this project was provided by the German Research Foundation, Deutsche Forschungsgemeinschaft (GRK2213) and Excellence Cluster Cardio-Pulmonary system (https://www.cpi-online.de) for MN, TH and FMS. The JSPS KAKENHI Grant Number JP17H03170 and JP17KK0128 for YK and YH. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.