Vascular Remodeling: The Multicellular Mechanisms of Pulmonary Hypertension
Abstract
:1. Introduction
2. Remodeling of the Vascular Wall
2.1. Endothelial Remodeling
2.1.1. Endothelial-Dysfunction-Related Factors
2.1.2. Hyperproliferation and Apoptosis of Endothelial Cells
2.1.3. Endothelial–Mesenchymal Transition
2.1.4. Endothelial Cell Activation and Thrombosis Formation
2.1.5. Endothelial Cell Heterogeneity
2.1.6. Endothelial Cell Metabolism and Epigenetics
2.2. Media Remodeling
2.2.1. Smooth Muscle Cell Phenotypic Transition
2.2.2. Proliferation of Pulmonary Artery Smooth Muscle Cells
2.2.3. Anti-Apoptosis in Smooth Muscle Cells and Reversal of Vascular Remodeling
2.2.4. Crosstalk Between Endothelial and Smooth Muscle Cells
2.3. Adventitial Remodeling
2.3.1. Activation of Fibroblasts
2.3.2. Phenotypic Changes in Fibroblasts
2.3.3. Crosstalk Among Fibroblasts, Endothelial Cells, and Smooth Muscle Cells
2.4. Extracellular Matrix Remodeling
2.4.1. Stiffness of the Extracellular Matrix
2.4.2. Inflammatory Response and the Extracellular Matrix
2.5. Immune Cells
2.5.1. T Cells
2.5.2. B Cells
2.5.3. Macrophages
2.5.4. Mast Cells
2.5.5. Dendritic Cells and Neutrophils
2.6. Progenitor Cells and Stem Cells
2.7. Pericytes
3. Conclusions
Author Contributions
Funding
Data Availability Statement
Conflicts of Interest
Abbreviations
PH | Pulmonary hypertension |
PVR | Pulmonary vascular resistance |
mPAP | Mean pulmonary artery pressure |
PAECs | Pulmonary artery endothelial cells |
PASMCs | Pulmonary artery smooth muscle cells |
PAAF | Pulmonary arterial adventitial fibroblast |
ESC | European Society of Cardiology |
ECM | Extracellular matrix |
HIF | Hypoxia-inducible factors |
ErbB3 | Human epidermal growth factor receptor 3, also recognized as HER3 |
YB-1 | Y-box binding protein 1 |
VHL | Von Hippel–Lindau |
VEGF | Vascular endothelial growth factor |
BMPR2 | Bone morphogenetic protein receptor 2 |
NO | Nitric oxide |
NOS | Nitric oxide synthase |
cGMP | Cyclic guanosine monophosphate |
FOX | Forkhead box protein |
EndMT | Endothelial–mesenchymal transition |
NET | Neutrophil extracellular trap |
EGF | Epidermal growth factor |
α-SMA | α-smooth muscle actin |
SM22α | Smooth muscle protein 22α |
TGF | Transforming growth factor |
IL | Interleukin |
BMP | Bone morphogenetic proteins |
NF-κB | Nuclear Factor-kappa B |
SCA | Stem cell antigen |
ENG | Endothelial glycoprotein |
vWF | Via vascular hemophilic factor |
TF | Tissue factor |
DHA | Docosahexaenoic acid |
TxA 2 | Thromboxane A2 |
CXCL | C-X-C chemokine ligand |
CXCR | C-X-C chemokine receptor |
CCL | C-C motif chemokine ligand |
MMP | Matrix metalloproteinases |
KLF | Kruppel-like factor |
ECs | Endothelial cells |
EPC | Endothelial progenitor cell |
SMCs | Smooth muscle cells |
ERS | European Respiratory Society |
VEGFR | Vascular endothelial growth factor receptor |
BMPs | Bone morphogenetic proteins |
eNOS | Endothelial nitric oxide synthase |
EGFR | Epidermal growth factor receptor |
FSP | Fibroblast-specific protein |
FAP | Fibroblast activation protein |
CaN | Calcineurin |
NFAT | Nuclear factor of activated T-cells |
ADP | Adenosine diphosphate |
EPA | Eicosapentaenoic acid |
EVs | Extracellular vesicles |
PLCγ1 | Phospholipase C gamma 1 |
ET-1 | Endothelin-1 |
KLF | Kruppel-like factor |
FOXO1 | Forkhead box protein 1 |
FOXM1 | Forkhead box protein M1 |
FGF | Fibroblast growth factors |
PDGF | Platelet-derived growth factor |
MSC | Mesenchymal stem cell |
CXCR | CXC chemokine receptor |
CXCL | (C-X-C motif) ligand |
PKM2 | Pyruvate kinase M2 |
CCL | Chemokine (C-C motif) ligand |
PTBP1 | Polypyrimidine tract-binding protein 1 |
PPAR-γ | Peroxisome proliferator-activated receptor γ |
PDGF-BB | Platelet-derived growth factor-BB |
TRPC | Transient receptor potential canonical |
PGI2 | Prostacyclin |
TGF | Transforming growth factor |
FGFR | Fibroblast growth factor receptor |
CO | Carbon monoxide |
HO-1 | Heme oxygenase 1 |
MCP-1 | Monocyte chemoattractant protein-1 |
PTX3 | Pentraxin 3 |
PA | Pulmonary artery |
BM | Basement membrane |
MMPs | Matrix metalloproteinases |
LOX | Lysyl oxidase |
TIMPs | Tissue inhibitors of metalloproteinase |
COX-2 | Cyclooxygenase-2 |
PGE2 | Prostaglandin E2 |
DCs | Dendritic cells |
TNF | Tumor necrosis factor |
IFN-γ | Interferon-gamma |
MCT | Monocrotaline |
LTB4 | Leukotriene B4 |
NETs | Neutrophil extracellular traps |
NE | Neutrophil elastase |
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Group | Clinical Classification | Clinical Subtype | Therapeutic Drugs |
---|---|---|---|
1 | Pulmonary arterial hypertension | Idiopathic, heritable, drug- and toxin-induced, venous/capillary (PVOD/PCH) involvement, viral (HIV) or parasitic disease (schistosomiasis), connective tissue disorders, liver cirrhosis, congenital heart disease, schistosomiasis, persistent PH of the newborn | CCBs (nifedipine, diltiazem, amlodipine), endothelin receptor antagonists, Ambrisentan, Bosentan, macitentan, PDE5i and guanylate cyclase stimulators (Sildenafifil, Tadalafifil, Riociguat), prostacyclin analogues and prostacyclin receptor agonists (Epoprostenol, Iloprost, Treprostinil, Beraprost, Selexipag) |
2 | PH associated with left heart failure | Left-sided atrial, ventricular, or valvular disease | Diuretics, PDE5i (e.g., Sildenafil) |
3 | PH associated with chronic hypoxemic lung disease | COPD, interstitial lung disease, obstructive sleep apnea, high altitude, developmental lung disorders | Treprostinil, PDE5is |
4 | PH associated with pulmonary artery obstructions | Pulmonary emboli, pulmonary hemangioma, pulmonary vasculitis, congenital pulmonary stenosis | VKAs, Riociguat, Treprostinil s.c., PDE5is (e.g., Sildenafifil), ERAs (e.g., Bosentan) |
5 | PH with unclear and/or multifactorial mechanisms | Sickle cell disease, sarcoidosis, metabolic disorders, renal failure, fibrosing mediastinitis | —— |
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Dai, J.; Chen, H.; Fang, J.; Wu, S.; Jia, Z. Vascular Remodeling: The Multicellular Mechanisms of Pulmonary Hypertension. Int. J. Mol. Sci. 2025, 26, 4265. https://doi.org/10.3390/ijms26094265
Dai J, Chen H, Fang J, Wu S, Jia Z. Vascular Remodeling: The Multicellular Mechanisms of Pulmonary Hypertension. International Journal of Molecular Sciences. 2025; 26(9):4265. https://doi.org/10.3390/ijms26094265
Chicago/Turabian StyleDai, Jinjin, Hongyang Chen, Jindong Fang, Shiguo Wu, and Zhuangzhuang Jia. 2025. "Vascular Remodeling: The Multicellular Mechanisms of Pulmonary Hypertension" International Journal of Molecular Sciences 26, no. 9: 4265. https://doi.org/10.3390/ijms26094265
APA StyleDai, J., Chen, H., Fang, J., Wu, S., & Jia, Z. (2025). Vascular Remodeling: The Multicellular Mechanisms of Pulmonary Hypertension. International Journal of Molecular Sciences, 26(9), 4265. https://doi.org/10.3390/ijms26094265