Resolving the design principles that control post-natal vascular growth and scaling.

After birth, tissues grow until they reach adult size, with each organ exhibiting unique cellular dynamics, growth patterns, and stem or non-stem cell sources. Using multiscale experimental and computational approaches, we found that aortic enlargement follows distinct growth principles, scaling with the vertebral column. Expansion proceeds via two temporally coordinated, spatially stochastic waves of proliferation aligned with blood flow, each with unique cell-cycle kinetics, with the first wave featuring cycles as short as 6 h. Single-cell RNA sequencing revealed increased fatty acid metabolism accompanying cell enlargement. Mathematical modeling and experiments showed that endothelial cell extrusion is essential for maintaining homeostatic aortic size as it adjusts for proliferation excess. Using a genetic model of achondroplasia, we mechanistically demonstrated that the aorta preserves proper scaling by increasing cell extrusion while keeping proliferation rates intact. These findings provide a blueprint of the principles orchestrating aortic growth, which relies entirely on the proliferation of resident differentiated cells. A record of this paper's transparent peer review process is included in the supplemental information.