. 2023 Jul 5;21:441. doi: 10.1186/s12967-023-04286-1

Table 1.

Mitochondrial-related proteins that involved in angiogenesis and endothelial function in various ECs, animal models or clinical trials under different stimulations were reviewed and summarized

Localization	Protein	Stimuli	Role in angiogenesis	Cell types	Animal model/clinical trials	References
^OMM
	SIRT3	CRIF1 deficiency, high glucose, hypoxia, angiotensin II	SIRT3 knockout exhibited higher ROS formation and OCR, decreased PFKFB3−dependent glycolysis, reduced VEGF and angiogenesis; suppressed reendothelialization capacity in EPCs, induced premature senescence, accelerated Ang II−induced EndoMT. SIRT3 overexpression promotes proliferation, migration, vessel sprouting and tube formation through VEGFR3 and ERK pathways and PINK1/Parkin−mediated mitophagy	MECs, EPCs CMECs, LECs, HUVECs, MAECs	Hypertension patients, KO and OE mice	[204, 205, 207–210]
	SIRT4	LPS	SIRT4 knockdown increased the pro−inflammatory cytokines IL−1β, IL−6 and IL−8 through activation of NF−kB, promoted MMP−9 and ICAM−1, while overexpression reversed these factors	HUVECs		[216]
	SIRT5	Ischemia–reperfusion, hypoxia	Downregulation of SIRT5 induced mitochondrial dysfunction, decreased angiogenic capacity and endothelial permeability, upregulated occludin and claudin−5, induced capillary rarefaction	HBMECs EPCs	KO mice, hypertensive patients	[221–223]
	Akap1	Hypoxia, femoral artery ligation	Akap1 inhibited VEGFR2 degradation through PKA/p38−dependent p−VEGFR2 at Y1173, Akap1 knockout decreased cell migration and proliferation, impaired blood flow and capillary density	HUVECs	KO mice	[242, 243]
	VDAC1		VDAC1 knockdown decreased ATP production and increased the AMP:ATP ratio, which in turn activated AMPK and phosphorylated raptor, inhibited mTOR activity and cell proliferation	HUVECs		[92]
	TSPO	Laser, hypoxia	TSPO KO decreased retina pro−angiogenesis and vascular leakage, increased glioma growth and angiogenesis by promoting glycolysis and reducing oxidative phosphorylation,	Phagocyte, GL261 cells, GBM1B cells	TSPO^KO mice	[116, 117]
	Drp1	Caffeine, hypoxia, replicative senescence, ischemia–reperfusion	Drp1 knockdown decreased lamellipodia formation, cell migration and proliferation via mitochondrial Ca²⁺ dependent pathway and impairment of autophagic flux. Drp1−C644A improved wound healing and angiogenesis in PDIA1 deficient mice. Inhibition of Drp1 phosphorylation at Ser616 preserving ischemia-reperfusion injury	HUVECs, PAECs CMECs	Mice under hindlimb ischemia, PDIA1 deficient mice, BI1 transgenic mouse	[167–171]
	Mfn1/2	VEGF	Knockdown of Mfn2 affected mtROS production, while knockdown of Mfn1 reduced NO signaling. Mfns are not regulated by angiogenic cues and dispensable for developmental angiogenesis	HUVECs, MPECs	Mfn1^KO mice	[164, 165]
	Fis1	Replicative senescence	Downregulation of Fis1 induced senescence and mitochondrial dysfunction, and impaired EPCs activity	EPCs	Hindlimb ischemic mice	[172]
	PINK1		PINK1 knockout reduced cardiac capillary density, increased oxidative stress and impaired mitochondrial function	Cardiomyocyte	KO mice	[144]
	Parkin		Parkin overexpression decreased eNOS expression and induced mitochondrial dysfunction by ubiquitination of ERRα	MAECs		[147]
	FUNDC1	VEGF	Deletion of FUNDC1 disrupted MAM formation and angiogenesis dependent on VEGFR2 expression through decreasing the binding of SRF to VEGFR2	HUVECs	EC−specific FUNDC1^KO mice	[154]
	BNIP3	Hypoxia	BNIP3 showed antagonistic effect with VEGF on ECs apoptosis under hypoxia	HPAECs, HUVECs and HLMECs		[163]
IMM
	^p66shc	^{Streptozotocin, VEGF, high glucose, age, ox−LDL, LDLC}	p66shc KO mice showed upregulation of eNOS and HO−1, prevented streptozotocin−induced endothelial dysfunction and oxidative stress. VEGF stimulation promotes pS36−pp66Shc formation through ERK/JNK/PKC, which involved in VEGF−induced VEGFR2 autophosphorylation. P66shc knockdown inhibited glucose−induced Rac1 activation and mitochondrial damage. P66shc inhibited the Ras−PI3K−Akt−eNOS−NO production. Acetylation of p66Shc promoted its p-S36. LDLC increased CpG hypomethylation and acetylation of histone 3 of p66shc promoter	HUVECs, HRECs, HAECs	p66shc^KO mice,	[36, 37, 39, 40, 42, 44, 45]
	UQCRB	Antimycin A	Inhibition of UQCRB reduced complex III enzyme activity, blocked mtROS−mediated VEGFR2, reduced EC proliferation, OCR and NAD⁺/NADH ratio, but not migration	HUVECs, QPC^KO lung ECs	QPC^KO mice	[49, 50]
	PHB1	VEGF, TGF−β1	Knockdown of PHB1 resulted in mitochondrial dysfunction and ROS production via inhibition of complex I, led to cytoskeletal rearrangements and cell senescence by increasing Akt and Rac1, reduced cell migration and tube formation. Activation of PHB ameliorated TGF−β−induced EndoMT	BAECs, HUVECs, HMECs	Transverse aortic constriction	[180, 181]
	UCP2	VEGF, ischemia, hypoxia	Overexpression UCP2 promoted tube formation in MAECs and BAECs, while knockdown UCP2 increased VEGFR2 phosphorylation and cell proliferation in HRMECs	MAECs, BAECs, HRMECs, MLECs	OIR model rat, AMPKα^KO mice, UCP OE and KO mice, MnSOD^+/− mice	[186, 188, 189]
	FECH	Hypoxia	FECH depletion decreased proliferation, migration and tube formation, suppressed p−VEGFR2 and VEGFR2, eNOS and HIF−1α, but did not affect macrovascular HUVECs proliferation	HRECs, HUVECs, HBMECs	L−CNV mice, Fechm1Pas mice model, OIR model	[247–249]
	OPA1		Promotion of angiogenesis by inhibiting NF−kB and maintaining cytosolic Ca²⁺ homeostasis through MCU1	HUVECs, MPECs	Opa1^iΔEC mice, OPA1^TG mice, Opa1^ΔEC/ΔEC mice	[164]
^{Matrix protein}
	MnSOD	High glocuse, non−reperfused myocardial infarction	H₂O₂ production by MnSOD promoted VEGF expression, cell sprouting and blood vessel formation by oxidation of PTEN. Knockdown of MnSOD reduced diabetic wound healing assays, MnSOD gene therapy restored angiogenesis and wound repair in diabetic mice. MnSOD promoted ECs proliferation and coronary angiogenesis, protected cardiac function in non−reperfused myocardial infarction	BLMC, EPCs MHECs	Diabetic mice, OE mice	[14–16]
	IDH2		IDH2 knockdown decreased expression of mitochondrial function, eNOS/NO production, induced endothelial inflammation via p66shc−mediated mitochondrial oxidative stress	HUVECs, MS1 cells, MLECs	IDH2^KO mice	[74, 75]
	ALDH2	Acetaldehyde, ischemia, hypoxia, β−amyloid, ethanol	Promotion of migration, proliferation and angiogenesis through improving mitochondrial function and HIF−1α−/VEGF−dependent mechanism. Hyperacetylation promoted ethanol−induced Akt−eNOS activation	HUVECs, HAECs	ALDH2^KO mice, CTO patients	[54, 57–59]
	CypD	VEGF, angiotensin II, IL17A, TNFα	CypD−deficient increased VEGF−induced proliferation and angiogenesis, while S−glutathionylation of CypD increased ROS production	HPAECs HPMECs, HAECs	CypD^KO mice	[100, 101]
Unknown
	FAM3A	Ischaemia, hypoxia, CoCl₂	Promoted capillary density and angiogenesis by enhancing CREB−dependent VEGFA transcription through ATP/P2 receptor/Ca2+ pathway	HUVECs	Hind limb ischaemia mice	[120]
	Trx2	VEGF, hypercholesterolemia, ischemia, TNF	Promotion of cell migration and survival by increasing NO bioavailability and inhibiting oxidative stress and ASK1−induced apoptosis	MAECs, MLMECs BAECs, HUVECs	Trx2^TG mice, ApoE−deficient mice, eNOS^KO, and eNOS^KO/Trx2^TG mice	[65–68]
	Cyp1B1		Cyp1B1 deficient impaired revascularization, eNOS and migration, increased oxidative stress and thrombospondin−2 in RECs, but increased VEGFR2 expression, cell proliferation and migration in LSECs	RECs, LSECs	Cyp1B1^KO mice	[229, 235]
	NRP1	Iron	NRP1 prevented iron−dependent mitochondrial superoxide production and premature senescence through interacting with the ABCB8	HMECs	NRP1^ECKO	[264]

MECs: microvascular endothelial cells; LECs: lung endothelial cells; HBMECs: human brain microvascular ECs; RMECs: retinal microvascular endothelial cells; MLECs: murine lung endothelial cells; HUVECs: human umbilical cord vein endothelial cells; PAECs: pulmonary artery endothelial cells, EPCs: endothelial progenitor cells; MAECs: mouse aortic endothelial cells; HPAECs: human pulmonary artery endothelial cells; HLMEC: human lung microvascular endothelial cells; BAECs: bovine aortic endothelial cells; LMECs: lung microvascular endothelial cells; CMECs: cardiac microvascular endothelial cells; MLMECs: mouse lung microvessel endothelial cells; HRECs: human retinal microvascular endothelial cells; HPMECs: human pulmonary microvascular endothelial cells; REC: retinal endothelial cells; LSEC: liver sinusoidal endothelial cells; MHECs: mouse heart endothelial cells; BLMCs: bovine lung microvessel cells; HAECs: human aortic endothelial cells; HMECs: human microvascular endothelial cells; MPECs: mouse pulmonary endothelial cells; MS1: mouse islet endothelial cells; PDIA1: protein disulfide isomerase A1; BI1: bax inhibitor 1; QPC: a subunit of the respiratory chain complex III. OIR: oxygen-induced retinopathy; L-CNV: laser-induced choroidal neovascularization; Fech^m1Pas: a partial loss-of-function M98K point mutation in the Fech gene; OPA1^iΔEC: an inducible endothelial knockout OPA1 mice. OPA1^ΔEC/ΔEC: EC Opa1 knockout mice; CTO patients: patients with chronic total occlusion. ABCB8: ATP-binding cassette B8. LDLC: low-density lipoprotein cholesterol; oxLDL: oxidized low density lipoprotein; MAM: mitochondria-associated endoplasmic reticulum membranes. SRF: serum response factor