Mechanical regulation of the early stages of angiogenesis

Abstract

Favouring or thwarting the development of a vascular network is essential in fields as diverse as oncology, cardiovascular disease or tissue engineering. As a result, understanding and controlling angiogenesis has become a major scientific challenge. Mechanical factors play a fundamental role in angiogenesis and can potentially be exploited for optimizing the architecture of the resulting vascular network. Largely focusing on in vitro systems but also supported by some in vivo evidence, the aim of this Highlight Review is dual. First, we describe the current knowledge with particular focus on the effects of fluid and solid mechanical stimuli on the early stages of the angiogenic process, most notably the destabilization of existing vessels and the initiation and elongation of new vessels. Second, we explore inherent difficulties in the field and propose future perspectives on the use of in vitro and physics-based modelling to overcome these difficulties.

Keywords: cell–matrix interaction; endothelial mechanobiology; shear stress; sprouting angiogenesis; transmural flow.

Figure 1.

Fluid mechanical (top half) and solid mechanical (bottom half) stimuli during the early stages of angiogenic sprouting. From left to right: destabilization, initiation and elongation. Cold colours represent fluid mechanical stimuli: liminal (blue), transmural (green) and interstitial (purple) flows and pressure; and warm colours, solid mechanical aspects: two-dimensional and three-dimensional stresses (maroon), cell–cell and cell–matrix interaction (orange) and cell stiffness (yellow).

Figure 2.

Specificities of some fluid mechanical stimuli. (a) Maximum shear stress is found at the base of sprouts when TF is considered: (i) schematic of luminal (LF) and transmural flows (TF), (ii, iii) flow velocity and resulting wall shear stress (WSS) fields (adapted from [90]). (b) Parallelism between the effects of IF around the entire microvessel and those of TF around a single EC. (c) IF generates opposite gradients of (i) matrix-bound (adapted from [156]—Copyright (2005) National Academy of Sciences, USA) and (ii) soluble (qualitative) VEGF isoforms. (d) Localization of hydrostatic pressure (HP) and interstitial pressure (IP). (e) Example waveforms of non-reversing pulsatile flow (NPF), reversing pulsatile flow (RPF) and oscillatory flow (OF).

Figure 3.

Specificities of some solid mechanical stimuli. (a) Effects of increased fibre density, stiffness and alignment on angiogenic sprouting (adapted from [275]). (b) Effects of ECM stiffness on cell–cell and cell–matrix junctions. (c) Different observed interactions between cell protrusions and the ECM: protrusion displacement in orange and matrix displacement in pink (adapted from [276]). (d) Tension in the sprout cell–cell junctions and forces between the tip cell and the extracellular matrix (ECM). The latter induces ECM fibre orientation.