Psycho-cardiovascular interaction network in cardiovascular health and disease: signaling pathways and molecular mechanisms

Figures

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  Figure 1. Overview of the psycho-cardiovascular interaction network (PCIN). PTSD: post-traumatic stress disorder; HPA: hypothalamic-pituitary-adrenal; ANS: autonomic nervous system; BDNF: brain-derived neurotrophic factor; PROK: prokineticin; PKR: prokineticin receptor; MAPK: mitogen-activated protein kinase; 5-HT: 5-hydroxytryptamine; NLRP3: NOD-like receptor protein 3.

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  Figure 2. Mechanisms of cardiovascular health regulation within the PCIN. HPA: hypothalamic-pituitary-adrenal; IL-6: interleukin-6; TNF-α: tumor necrosis factor-α; CRP: C-reactive protein; GC: glucocorticoid; ANS: autonomic nervous system; IR: insulin resistance; HDL: high-density lipoprotein; LDL: low-density lipoprotein.

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  Figure 3. BDNF pathway in the PCIN and its dual effects on neuropsychiatric and cardiovascular systems. BDNF is secreted from the endoplasmic reticulum in the precursor form pro-BDNF, which is cleaved by proteolytic enzymes to produce m-BDNF. The expression of BDNF can be upregulated by stimuli such as exercise, oxytocin, and antidepressant drugs, and inhibited by chronic stress. m-BDNF preferentially binds to the full-length receptor TrkB-FL. This triggers autophosphorylation and the activation of multiple pathways such as PLC-γ/IP3/CaMKII, PI3K/Akt, and MAPK, thereby exerting protective effects in neuropsychiatric and cardiovascular systems. Truncated TrkB isoforms (TrkB-T1/T2/Shc) lack kinase activity and can thus inhibit TrkB-FL signaling. Upon binding to the p75NTR–sortilin complex, pro-BDNF activates the JNK, NF-κB, and caspase-3 pathways, leading to apoptosis, neuroinflammation, and vascular injury. ER: endoplasmic reticulum; BDNF: brain-derived neurotrophic factor; TrkB: tropomyosin receptor kinase B; p75NTR: p75 neurotrophin receptor; JNK: c-Jun N-terminal kinase; NF-κB: nuclear factor-kappa B; PLC-γ: phospholipase C-γ; PI3K: phosphatidylinositol 3-kinase; MAPK: mitogen-activated…

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  Figure 4. PROK/PKR pathway in PCIN. A. PROK/PKR signaling pathway; B. The effect of PROK2/PKR2 in the neuropsychiatric system; C. The effect of PROK2/PKR2 in the cardiovascular system. (A) PROK1 and PROK2 perform their biological functions and mediate multiple downstream signaling pathways by interacting with the PKR1 and PKR2 receptors, with PROK2 having a higher affinity for PKR1. PKR1/2 can activate the PLC-IP3-Ca2+ pathway and induce PKCε translocation via Gq/11, which enhances TRPV1 activity and leads to hyperalgesia. PKR1/2 can also activate the PI3K/Akt and MAPK/ERK pathways via Gi/o, thereby promoting cell survival, proliferation, and differentiation, and promote cAMP accumulation via Gs. PKR2 also inhibits ZO-1 protein expression via G12, which increases vascular permeability and induces endothelial cell fenestration.(B)PROK2 can upregulate TSHZ1 via PKR2, and regulate neuronal migration, GnRH neuron survival and GABA current inhibition. In the adult mouse brain, PKR2+ neural progenitor cells migrate from the SVZ to the OB along the RMS, and PROK2 acts as a chemokine to induce their migration. Abnormalities in their function have been associated with Kallmann syndrome, depression,…

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  Figure 5. MAPK pathway in PCIN and its dual effects on neuropsychiatric and cardiovascular systems. The MAPK pathway mediates pathophysiological changes in the CNS and cardiovascular system. In the CNS, stimuli such as neuroinflammation, excitotoxicity, oxidative stress, cerebral ischemia, and psychological stress activate the MAPK cascade; in the cardiovascular system, the pathway is triggered by mechanical stress, ischemia-hypoxia, and inflammatory factors. These stimuli induce signals that are propagated through a three-tiered kinase cascade and ultimately activate members of the four major MAPK subgroups (ERK1/2, JNK, p38, and ERK5). Activated MAPK signaling can act on neurons, glial cells, cardiomyocytes, and VECs, leading to depression, anxiety, and PTSD in the neuropsychiatric system, and myocardial fibrosis, atherosclerosis, and myocardial infarction in the cardiovascular system. MAPK pathway could be potential therapeutic targets. CNS: central nervous system; MAPK: mitogen-activated protein kinase; MAPKK: MAPK kinase; MAPKKK: MAPK kinase kinase; ERK: extracellular signal-regulated kinase; JNK: c-Jun N-terminal kinase; VECs: vascular endothelial cells; PTSD: post-traumatic stress…

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  Figure 6. 5-HT/5-HT2A-R pathway in PCIN. A. 5-HT2A-R signaling pathway; B. The effect of 5-HT2A-R in PFC; C. The effect of 5-HT2A-R in the cardiovascular system; D. The mechanisms of 5-HT signaling linking neuropsychiatric and cardiovascular systems; E. Psychologically mediated cardiovascular dysfunction through central and peripheral 5-HT2A-R.(A) Binding of 5-HT to 5-HT2A-R results in activation of PLC, which hydrolyzes PIP2 to generate IP3 and DAG. IP3 promotes calcium release, whereas DAG activates PKC. (B) In the PFC, 5-HT2A-R activates calmodulin phosphatase via PLC-IP3-Ca2+ signaling, inhibits Cav1.2 L-type calcium channels, and regulates synaptic transmission and neuronal excitability. (C) In platelets, activated 5-HT2A-R promotes cPLA2 activation via PLC-IP3-Ca2+ to generate TXA2, whereas activation of integrin αIIbβ3 via PLC-DAG-PKC mediates platelet aggregation. In VSMC, 5-HT2A-R activation leads to the release of Ca2+. This leads to the formation of the Ca2+-CaM complex, which activates MLCK and Src/PI3K and mediates vasoconstriction and remodeling. oxLDL/fatty acids activate macrophage 5-HT2A-R, which upregulates GPAT1 and CD36 via the PLC-DAG-PKCε pathway, thereby promoting…

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  Figure 7. NLRP3 inflammasome pathway in PCIN and its dual effects on neuropsychiatric and cardiovascular systems. Psychological stress activates the HPA axis and induces excessive secretion of GC. This results in priming signals that activate NF-κB, upregulate the expression of NLRP3 proteins and pro-IL-1β, and promote the occurrence of PTMs in NLRP3. Psychological stress also induces ROS and ATP production, with ATP activating P2X7R and triggering K+ efflux, thereby promoting NLRP3 inflammasome activation. The activated NLRP3 recruits and activates caspase-1, which cleaves pro-IL-1β and pro-IL-18 to generate mature IL-1β and IL-18, and also cleaves GSDMD, leading to pyroptosis. This process can induce hippocampal inhibition, HPA axis disorders, and neuroinflammation, thus promoting the development of mental disorders; it can also act on cardiac fibroblasts, macrophages, endothelial cells, and cardiomyocytes, which promotes the onset and development of CVD. HPA: hypothalamic-pituitary-adrenal; GC: glucocorticoid; PTMs: post-translational modifications; NLRP3: NOD-like receptor protein 3; NF-κB: nuclear factor kappa B; ROS: reactive oxygen species; ATP: adenosine triphosphate; P2X7R:…

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  Figure 8. Potential therapeutic strategies targeting the PCIN and its molecular mechanisms. This figure demonstrates potential therapeutic strategies integrating heart–brain co-management concepts and their molecular mechanisms. Nonpharmacological treatments, including CBT and MBSR, produce both psychological and cardiovascular benefits by modulating the HPA axis, ANS, and anti-inflammatory effects. Pharmacological treatments include SSRIs, 5-HT2A-R antagonists, NLRP3 inhibitors, and TrkB agonists. SSRIs exert antiplatelet effects through inhibition of SERT, GPVI, and P2Y12 receptors, and improve endothelial function by increasing NOx. 5-HT2A-R antagonists block the downstream CaMKII/HDAC4 phosphorylation cascade, reduce pathological gene transcription, and improve cardiac remodeling. Ideal NLRP3 inhibitors and TrkB agonists should possess good blood-brain barrier permeability and exert dual neurocardiovascular protective effects on the CNS and peripheral tissues. AAV-mediated gene therapy has demonstrated good prospects for targeted therapies with greater precision. CBT: cognitive behavioral therapy; MBSR: mindfulness-based stress reduction; HPA: hypothalamic-pituitary-adrenal; ANS:…