Biophysique de l'angiogenèse par bourgeonnement : une perspective nématique

Angiogenesis, the formation of microvessels from pre-existing blood vessels, plays a crucial role in both physiological and pathological settings. Angiogenesis is undesirable in the context of cancer, where tumors too large to rely on diffusion need it for survival. On the contrary, in cardiovascular issues like coronary artery blockage, angiogenesis is fundamental for recovery, since it helps provide blood flow to the heart, reducing tissue damage. Understanding the mechanisms regulating angiogenesis is thus vital.Angiogenesis begins with the formation of small vessel sprouts from existing blood vessels, which grow, branch, and fuse to create complex microvascular networks. This process is triggered when vascular endothelial cells receive signals that alter their activity. It has long been known that chemical signals like vascular endothelial growth factor can initiate angiogenic sprouting. More recently, however it has become clear that the mechanical environment of blood vessels also plays a key role in determining and shaping angiogenic sprouting.To the best of our knowledge, no unified framework has yet been established to explain how individual or combined cues drive angiogenesis. Interestingly, the early stages of sprouting angiogenesis bear a striking resemblance to other morphogenetic processes like epithelial cell extrusion, the formation of myoblast mounds, and hydra morphogenesis, all of which have recently been interpreted through the lens of active nematic liquid crystals. Active matter is made up of particles that consume energy to exert forces. These particles can behave like liquid crystals, which represent an intermediate state of matter between crystalline solids and isotropic liquids. In particular, nematic phases are characterized by long-range orientational order, i.e. the particles align preferentially along a preferred direction, while lacking positional order, thus retaining a fluid-like behavior.Inspired by this evidence, in this study, we use in vitro experiments to investigate endothelial behavior at the onset of angiogenesis. We observe how VEGF stimulation drives the emergence of distinct patterns, with ECs organizing into elongated cell streams that coexist with more polygonal regions. Notably, we find that angiogenic sprouting preferentially initiates at the tips of these streams, that we term wedges. Wedges correspond to regions of high distortion in the nematic order. By examining the mechanical environment around these structures, we uncover distinct forces and deformations that are consistent with the aforementioned framework. Further analysis reveals that the formation of these organized cell streams arises from a delicate balance between microtubule polymerization and actomyosin contractility. Additionally, when this balance is disrupted, we observe the appearance of topological defects with vortex-like configurations and significant changes in substrate deformation.These findings emphasize the crucial role of nematic distortions in driving angiogenic sprouting and suggest new possibilities for therapeutic intervention. As a step in this direction, we demonstrate how geometric and mechanical manipulation can be leveraged to control the angiogenic response, paving the way for novel approaches in vascular engineering.