. 2023 Sep 29;14:1244098. doi: 10.3389/fphar.2023.1244098

TABLE 2.

Overview of the pleiotropic effects of rivaroxaban in endothelial cells (ECs) in vitro.

Endothelial cell type	Rivaroxaban dose	Stimulation factor	Cellular effects of rivaroxaban	Biological/Pleiotropic effects	Reference
EA.hy926	500 nM	FXa	↑ Tube formation	Angiogenic effects	Lange et al. (2014)
HUVECs	10 μM	FXa (10 nM)	↑ Proliferation	Proliferative action	Sanada et al. (2016)
			↑ Tubular length	Angiogenic effects
			↓CDKN2A, CDKN1C, EGR1, IGFBP-5, IL-1β, IL-6, CCL2, ICAM1 expression	Anti-inflammatory effects
HUVECs	500 nM	FXa (50 and 100 nM)	↓ ICAM1, CCL2, IL-8 expression	Anti-inflammatory effects	Seki et al. (2017)
HUVECs	500 nM	FXa (50 and 100 nM)	↓ CCL2 secretion	Anti-inflammatory effects	Seki et al. (2017)
HaECs	1 μM	FXa (50 nM)	↓ IL-1β, IL-6, IL-8, CCL2, ICAM1, VCAM1, MMP2 expression	Anti-inflammatory effects	Ding et al. (2021)
HaECs	1 μM	FXa (50 nM)	↓ Monocytes adhesion to ECs	Anti-inflammatory effects	Ding et al. (2021)
HUVECs	50 nM	FXa (9 nM)	↑ Proliferation	Proliferative action	Álvarez et al. (2018)
			↑ Migration	Angiogenic effects
			↓ EDN2, SELE, CCL5, VCAM1, MMP2, u-PA expression, platelet adhesion	Anti-inflammatory effects
			↑ u-PA activity	Anti-inflammatory effects
HCAECs and HDBECs	137.9, 1379 nM	FXa (10 nM)	↓ Endothelial permeability	Stabilizes endothelial integrity	Benelhaj et al. (2019)
HUVECs	30 nM	AGEs + 3% citrated-plasma	↓ MOK, CCL2, ICAM expression	Anti-inflammatory effects	Ishibashi et al. (2014)
HUVECs	30 nM	AGEs + 3% citrated-plasma	↓ ROS generation, THP-1 cell adhesion	Anti-oxidant effects	Ishibashi et al. (2014)
HUVECs	30 nM + Ang II	AGEs	↑TFPI expression and activity	Angiotensin II-mediated anticoagulant effects	Yang et al. (2017)
HUVECs	50, 500 nM	High glucose (22 mM)	↓ Senescence, p53, p16 expression	Anti-senescence effects	Maeda et al. (2019)
			↑ Telomerase activity and telomere length	Anti-senescence effects
			↑ NOx, NOS3 expression	Anti-atherosclerotic effects
			↓ ROS generation, p22^phox, ICAM1, VCAM1, PAR-1 expression	Anti-atherosclerotic effects
HCAECs	50 nM + Aspirin	D-Glucose (30 mM)	↑ PRKN, PINK1 expression	Promote mitophagy	Zekri-Nechar et al. (2022a)
HCAECs	50 nM + Aspirin	D-Glucose (30 mM)	↓ ROS generation	Anti-oxidant effects	Zekri-Nechar et al. (2022a)
EPCs	5, 10, 20 μM	High glucose (20 mM)	↑ Proliferation, migration, tube formation, NOS3, AKT1, p-NOS3, VEGFA expression	Angiogenic effects on diabetes	Wu et al. (2015)
EPCs	5, 10, 20 μM	High glucose (20 mM)	↓ Senescence	Angiogenic effects on diabetes	Wu et al. (2015)
HCMECs	1 μM	Hypoxia	↓ PAR-2, MAPK1/2, NF-κB expression	Anti-fibrotic and anti-oxidant effects	Imano et al. (2018)
HCMECs	1 μM	Hypoxia + sugen5416	↓ PAR-2, p-JNK, p-SMAD3, p-ERK-1/2, p-NF-kB expression	Anti-fibrotic effects	Imano et al. (2021)
HUVECs	920 nM	Hypoxia-reoxygenation (H/R)	No effect on ICAM1 and VCAM1, THBD, and EPCR expression	No protective impact on H/R conditions	Guillou et al. (2020)
HUVECs	229, 1150 nM	25-hydroxycholesterol (25 μΜ)	↓Endothelial permeability, TF, ICAM1, VEGFA, IL-33, CCL2, TNF expression	Stabilizes endothelial integrity, anti-inflammatory effects	Gorzelak-Pabis et al. (2021)
HUVECs	229, 1150 nM	25-hydroxycholesterol (25 μΜ)	↑ CDH5 expression	Stabilizes endothelial integrity, anti-inflammatory effects	Gorzelak-Pabis et al. (2021)
HUVECs	1 μM	FXa (10 nM) + LPS	↓ PAR-2, NF-κB, IL-1b, TNF, IL-6, p-MAP3K7, p-P65 expression, apoptosis, migration, permeability	Anti-inflammatory effects on ALI	Shi et al. (2018)
HUVECs	1 μM	FXa (10 nM) + LPS	↑Viability	Anti-inflammatory effects on ALI	Shi et al. (2018)
HPMEC	50 nM	LPS (1 μg/mL) + SARS-CoV-2 Subunits S1 and S2 (10 nM)	↑ Mitochondrial membrane potential	Covid-19-induced mitochondrial shift prevention effects	Zekri-Nechar et al. (2022b)
HPMEC	50 nM	LPS (1 μg/mL) + SARS-CoV-2 Subunits S1 and S2 (10 nM)	↓Cytochrome C oxidase activity, LDH activity, UCP2 expression	Covid-19-induced mitochondrial shift prevention effects	Zekri-Nechar et al. (2022b)
HBEC-5i + Human Astrocytes	10 μM	NA	P-gp and BRCA-mediated BBB transportation	ABC transportation	Puech et al. (2018)

EA.hy926, Immortalized Human Umbilical Vein Endothelial Cell Line; HUVECs, Human Umbilical Vein Endothelial Cells; HaECs, Human Aortic Endothelial Cells; HCAECs, Human Coronary Artery Endothelial Cells; HDBECs, Human Dermal Blood Endothelial Cells; HCMECs, Human Cardiac Microvascular Endothelial Cells; EPCs, Endothelial Progenitor Cells; HPMEC, Human Pulmonary Microvascular Endothelial Cells; HBEC-5i, Human Brain Endothelial Cells-5 immortalized; FXa, Factor Xa; AGEs, Advanced Glycation End Products; LPS, Lipopolysaccharide; SARS-CoV-2, Severe Acute Respiratory Syndrome Coronavirus 2; CDKN2A, Cyclin-Dependent Kinase Inhibitor 2A; CDKN1C, Cyclin-Dependent Kinase Inhibitor 1C; EGR1, Early Growth Response 1; IGFBP-5, Insulin-Like Growth Factor-Binding Protein 5; IL-1β, Interleukin-1 beta; CCL2, C-C Motif Chemokine Ligand 2; ICAM1, Intercellular Adhesion Molecule-1; VCAM1, Vascular Cell Adhesion Molecule-1; MMP2, Matrix Metalloproteinase-2; EDN2, Endothelin-2; SELE, Selectin E; u-PA, urokinase Plasminogen Activator; MOK, Mitogen-Activated Protein Kinase Kinase; ROS, Reactive Oxygen Species; THP-1, Human Monocytic Cell Line; TFPI, Tissue Factor Pathway Inhibitor; NOx, Nitrogen Oxides; NOS3, Nitric Oxide Synthase 3; PRKN, Parkin RBR E3 Ubiquitin Protein Ligase; PINK1, PTEN-Induced Kinase 1; AKT1, Protein Kinase B; VEGFA, Vascular Endothelial Growth Factor A; PAR, Proteinase-Activated Receptor; p-MAPK1/2, Phosphorylated Mitogen-Activated Protein Kinase 1/2; NF-κB, Nuclear Factor Kappa B; JNK, c-Jun N-Terminal Kinase; SMAD3, Mothers Against Decapentaplegic Homolog 3; ERK-1/2, Extracellular Signal-Regulated Kinase 1/2; EPCR, Endothelial Protein C Receptor; TF, Tissue Factor; TNF, Tumor Necrosis Factor; CDH5, Cadherin 5; LDH, Lactate Dehydrogenase; UCP2, Uncoupling Protein 2; P-gp, P-Glycoprotein; BRCA, Breast Cancer Resistance Protein; BBB, Blood-Brain Barrier; ALI, Acute Lung Injury; COVID-19, Coronavirus Disease 2019; ABC, ATP-Binding Cassette.