<strong>Supplementary figure S2. Ang II/AT1R-mediated modulation of RhoA/ROCK, </strong>based on established pathways in blood vascular (patho)physiology.

Key molecular nodes that are expressed not only in arteries (red) but also in lymphatics (green) and could participate in similar signaling are highlighted. Sharp arrows: activation/stimulation; dashed arrows: inhibition. Rho-associated coiled-coil kinase (ROCK) is activated by AT1R via Gαq , that in turn activates the Rho-guanine exchange factors (RhoGEFs) and RhoA. This activation cascade is controlled by AT1R-induced activation of RGS proteins, providing a negative feedback to the system. ROCK phosphorylates and activates MYPT-1, an inhibitor of the myosin light chain phosphatase (MLCP), which would normally dephosphorylates the myosin light chain (MLC) and induces smooth muscle relaxation. Inhibition of MLCP by a ROCK-activated MYPT-1maintains MLC in the phosphorylated, pro-contractile state induced by MLC kinase (MLCK). The persistence of MLC in the phosphorylated state can be linked to Ang II also through Gαq-mediated activation of phospholipase C (PLC), which hydrolyzes phosphatidylinositol 4,5-bisphosphate (PIP2), releases inositol,1,4,5 trisphosphate (IP3), promotes Ca2+ release from the endoplasmic reticulum and eventually Ca2+-dependent activation of calmodulin (CaM). CaM is an activator of MLCK. In addition, ROCK signaling sits at the intersect with VEGF-A/VEGFR2, with seeminglyopposite effects between blood and lymphatic vessels. Please see main text for details. For this figure, we acknowledge the use of Servier Medical Art by Servier, which is licensed under a Creative Commons Attribution 3.0 Unported License.