Development of vascular myogenic responses in zebrafish

The vascular system is placed under enormous stress at the onset of cardiac contractility and blood flow. Nascent blood vessel tubes initially consist of a thin endothelial wall and rapidly acquire support from mural cells (pericytes and vascular smooth muscle cells; vSMCs). Following their association with vessels, mural cells acquire vasoactive ability (contraction and relaxation). However, we have little information as to when this vasoactivity first develops, and the extent to which each mural cell type contributes to vascular tone regulation during development. For the first time in an in vivo system, we highlight the dynamic changes in mural cell vasoactivity during development. We assess mural cell vasoactivity in the early zebrafish cerebral vasculature in response to pharmacological agents. We determine that pericyte-covered vessels constrict and dilate at 4 days post fertilization (dpf) but not at 6 dpf. The prostaglandin EP4 receptor contributes to pericyte-covered vessel dilation at 4 dpf. In contrast, vSMC-covered vessels constrict but do not dilate at 4 dpf. At 6 dpf, vSMC-covered vessels continue to constrict but only dilate from a pre-constricted state. Using genetic ablation, we demonstrate that mural cell contraction and relaxation is an active response by pericytes and vSMCs. Thus, we show that both pericytes and vSMCs have the ability to regulate cerebral vascular tone but at different stages of development. Pericytes are involved in regulating vessel diameters prior to the maturation of the vSMCs. Once vSMCs mature, pericytes are no longer active, and only vSMCs regulate vascular tone in the developing embryonic brain of zebrafish. The onset of vasoactivity of vSMCs corresponds to the development of increased neuronal activity and neurovascular coupling.