<strong>Supplementary figure S3. Ang II/AT1R-mediated modulation of eNOS activity, </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. In endothelial cells, RAS overall reduces eNOS activity and this occurs through different interconnected mechanisms: direct ROS-mediated activation of the proline-rich tyrosine kinase 2 (PYK2); ROS-induced activation of protein phosphatase 2A (PP2A); Gαq/PLC/PKC inhibitory cascade; inhibition of the eNOS activating PI3K/AKT pathway via direct stimulation of the G protein-coupled receptor kinase 2 (GRK2) and ROCK signaling. These mechanisms prevent eNOS to to generate L-citrulline and nitric oxide (NO) from L-arginine. In muscle cells, NO diffusing from the endothelium would modulate vascular tone via cGMP-mediated activation of the protein kinase G (PKG), that in turn prevents IP3R-induced Ca2+ release from the sarcoplasmic reticulum, promotes Ca2+ reuptake by the sarco/endoplasmic reticulum calcium ATPase (SERCA) and negatively regulated Ca2+ influx via voltage-dependent calcium channels (VDCC). Therefore, the Ang II/AT1R-mediated reduction in NO availability opposes relaxation. Please eee 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.