Vascular Injury Changes Topology of Vessel Network to Adapt to Partition of Blood Flow for New Arteriovenous Specification

Abstract

Within vascular networks, wall shear stress (WSS) modulates endothelial cell proliferation and arteriovenous specification. Mechano-responsive signaling pathways enable vessels within a connected network to structurally adapt to properly partition blood flow between different parts of organ systems. Here, we study vascular regeneration in a zebrafish model system, performing tail amputation of the Dorsal Aorta (DA)-Posterior Cardinal Vein (PCV) embryonic circulatory loop (ECL) at 3 days post fertilization (dpf). Following severing the ECL, the topology of the micro-circular network is reorganized to engender local increase in blood flow and peak WSS in the closest Segmental Artery (SeA) to the amputation site. Remodeling of this artery increases its radius, and blood flow. These hemodynamic WSS cues activate post-angiogenic Notch-ephrinb2 signaling to guide network reconnection and restore microcirculation. Gain- and loss-of-function analyses of Notch and ephrinb2 pathways, manipulations of WSS by modulating myocardial contractility and blood viscosity directly implicate that hemodynamically activated post-angiogenic Notch-ephrinb2 signaling guides network reconnection and restore microcirculation. Taken together, amputation of the DA-PCV loop induces changes in microvascular topology to partition blood flow and increase WSS-mediated Notch-ephrinb2 pathway, driving the new DLAV-PCV loop formation for restoring local microcirculation.