1. Ang II mediated pathways involved in pulmonary vasoconstriction: increased cytosolic calcium via direct:(1a) Ang II/AT1R/PLC/Ca2+-Calmodulin pathway) or indirect pathways: (1b) AT1R/NOX/ROS/cADPR/CCE/Ca2+ pathway;(1c) Ang II/AT1R/Erk1/2/DNMT/SOD2 pathway (pseudohypoxia) results in activation of myosin light chains. This along with Rho-mediated inhibition of myosin light chain phosphatases result in actin-myosin coupling and vasoconstriction (1d) Ang II/AT1R/Rho/ROCK pathway (1e) Increased superoxide-mediated uncoupling of NO results in reduced bioavailability of NO and inhibits vasodilation and produce pro-thrombotic activity.
2. Warburg phenomenon and pseudohypoxia state: (2a) Ang II/AT1R/Erk1/2/DNMT/SOD2/HIF 1α/PDK pathway induces hypermethylation of a CpG island in the SOD2 promoter results reduced SOD 2 activity, decreased mitochondrial H₂O₂production with increase in mitochondrial superoxide levels resulting in normoxaic stabilization of HIF1α and uncoupled glycolysis. Reduced H₂O₂ is coupled with less oxidized redox state, closure of Kv channels with increased opening of type-L Ca²⁺ channels and raised cytosolic Ca²⁺ influx with decreased mito Ca²⁺. Other pathways that results in stabilization of HIF1α: (2b) Ang-II/Erk2/Dpr-1 pathway (2c)PI3K/Akt/FOXO3/SOD2 pathway and (2d) NOX/ROS/SIRT 3/FOXO 3/SOD 2 pathway
3. Mitochondrial biogenesis impairment: Reduced SITR3 activity results in reduced acetylation of FOXO3 and increased phosphorylated form of FOXO3. This reduced nuclear translocation of FOXO3 with reduced transcription of antioxidant enzymes (SOD2, Prx 3, Prx 5, Trx 2). Unopposed superoxide activity also results in impaired mitochondrial biogenesis
4. Increased mitochondrial fission/reduced mitochondrial fusion:reduced SIRT 3/PGC-1α/TFAM and (4a) increased (4b)STAT 3 pathways activates Dynamin-related protein (Drp-1) activating kinases including Erk 2 and results in Drp-1 mediated increased mitochondrial fission, impaired apoptosis and increased proliferative angiogenesis. (4c) Ang-II/Erk2/Dpr-1 pathway
5. Positive feed-forward or feed-back pathways resulting in vicious cycle: (5a) AT1R/HIF-1α/ACE/Ang II/Ca²⁺loop via PI3K/Akt pathway and STAT3 pathway fostering VEGF synthesis(5b) Ca2+ mediated Ca²⁺ entry further increasing cytosolic Ca²⁺ (5c) A II/NOX/ROS/c-Src/NOX pathway and (5d) Ang II/NOX/ROS/RNS/mtK_ATP /ROS pathway generating more ROS resulting in opening of mPTP channels and abrupt collapse of Δψm. RNS are associated with increased cytotoxic effects and platelet activation (not described in the Figure)