This schema focuses on factors causing increased SMC and fibroblast proliferation as well as apoptosis of ECs, causing an initial reduction in vessel number, followed by proliferation of apoptosis-resistant ECs in plexiform lesions. It shows multiple levels of interaction, with numerous factors related as described in the text. For example, serotonin stimulates both PDGF-mediated and S100A4/Mts1-mediated SMC and fibroblast proliferation and it also reduces Kv channel function, as does hyperpolarized mitochondria. BMPRII dysfunction causes Kv channel dysfunction and enhances TRP channel activity, which increases intracellular calcium levels, and may (as reflected by question mark) induce elastase activity. Viruses of the herpes family can induce elastase activity. Elastase, via activation of MMPs and tenascin C (TN-C), upregulates growth factor (GF) receptors such as EGF receptors (EGFRs) and also triggers release of growth factors such as EGF from the extracellular matrix, all of which leads to SMC proliferation. BMPRII dysfunction can also increase PDGF activity, increase SMC proliferation by suppressing PPARγ, and increase TGF-β activity. BMPRII dysfunction can enhance inflammation via osteoprotegrin and IL-6. NFATc2 can suppress Kv channel function. Other inflammatory mediators such as fractalkine and MCP-1 can, in addition to osteoprotegrin and IL-6, increase SMC proliferation. BMPRII dysfunction can lead to EC apoptosis, as can elastase activity. EC apoptosis may predispose to the development of apoptosis-resistant ECs in plexiform lesions. MCP-1, mast cell proteinase 1; TRP, transient receptor potential Ca²⁺ channels.