Background: Vascular network formation induced by angiogenesis plays an
important role in many physiological and pathological processes. However, the role of
blood flow and underlying mechanisms in vascular network formation, for example for
the development of the caudal vein plexus (CVP), is poorly understood.
Objective: The aim of this study was to explore the role of ERK5-klf2a-nos2b signaling
in the CVP angiogenesis.
Method and Results: In this study on tnnt2a-MO injection and chemical blood flow
modulator treatment in zebrafish embryos, we demonstrated that decreased blood flow
disrupted CVP formation. The hemodynamic force was quantitatively analyzed.
Furthermore, CVP angiogenesis in zebrafish embryos was inhibited by disruption of the
blood flow downstream effectors ERK5, klf2a, and nos2b in response to treatment with
the ERK5 specific inhibitor and to injection of klf2a-MO, nos2b-MO. Overexpression of
klf2a mRNA or nos2b mRNA restored vascular defects in tnnt2a or klf2a morphants. The
data suggest that flow-induced ERK5-klf2a-nos2b signaling is involved in CVP
angiogenesis in zebrafish embryos.
Conclusion: We have demonstrated that blood flow is essential for vascular network
formation, specifically for CVP angiogenesis in zebrafish. A novel genetic and
mechanical mechanism was discovered in which ERK5 facilitates the integration of
blood flow with the downstream klf2a-nos2b signaling for CVP angiogenesis.