Fig. 2. Roles of wall shear stress, metabolic, conducted and convected signals in structural adaptation.

(A,B) Local action of adaptive signals; (C,D) Modes of metabolic information transfer. Left column: mechanisms of signal generation. Center column: stimuli and responses. Dashed lines show feedback pathways (blunt heads indicate negative feedback). Right column: Significance for network properties. Flow directions are indicated by small black arrows. (A) Shear stress (τ) generated by flowing blood is sensed by endothelial cells and stimulates structural increase in diameter. For a given blood flow, shear stress decreases, giving a negative feedback. However, for a given driving pressure increased diameter will lead to increased flow, causing positive feedback. Shear stress response generates a progression from larger to smaller vessels correlated with flow rates in the arterial and venous trees. Transmural pressure difference leads to a circumferential wall stress (σ) which in turn stimulates diameter decrease. Wall stress response generates the arterio-venous asymmetry with small arterial and larger venous vessels. (B) Tissue hypoxia leads to release of metabolic signal substances that diffuse into blood and stimulate increased diameter and increased flow, which improves oxygen availability and may also lead to faster washout of metabolic signal substance. The metabolic response enables the vasculature to respond to tissue metabolic demands and stabilizes parallel flow pathways. (C) Conducted signals generated in distal vessels are propagated upstream to feeding arterioles (orange arrow). Short arterio-venous connections (green circle) remain small and do not form functional shunts. For conduction, it is relevant that signals travel only in the direction against the blood flow (upstream) and do not reenter smaller side-branches (blunted arrow). (D) In the downstream direction, convection of metabolic substances allows for information propagation to draining vessels.