Table 1.

Vascular protective agents in the role of ROP development.

Pathogenic Agents in ROP	Phase 1 in ROP Development	Phase 2 in ROP Development	Relevant Vascular Protective Agents in ROP Development (Phase of ROP)	Intervention	Animal Model	Beneficial Effect	Adverse Effect	Reference
VEGF	↓	↑	VEGF (Phase 1)	Intraocular injection	Rat OIR model	Prevention of apoptosis of vascular endothelial cells Reduction in avascular area	/	[16]
			Bevacizumab (Phase 2)	Intravitreal injection	(Clinical study)	Reduction of the avascular area and continuing vessels growth	Reduced systemic VEGF level after injection Influenced the long-term neurodevelopment	[17,18,19,20,21,22,23]
			Ranibizumab (Phase 2)	Intravitreal injection	(Clinical study)		/	[19,24,25]
			Aflibercept (Phase 2)	Intravitreal injection	Mouse OIR model		/	[26]
			VEGFA shRNA (Phase 2)	Subretinal injection	Rat OIR model	Reduced VEGF expression Inhibited neovascularization in short- and long-term studies	/	[27]
			Anti-KDR (Phase 2)	Surgical implantation	Dog OIR model	Suppressed neovascularization	/	[28]
			SRPIN340 (Phase 2)	Intraocular injection	Rat OIR model	Reduced VEGF expression	/	[29]
			Rapamycin (Phase 2)	Subcutaneous injection	Mouse OIR model	Reduced neovascularization	/	[30]
IGF-1	↓	↑	rhIGF-1 (Phase 1)	Intraperitoneal injection	Mouse OIR model	Higher score in maturation assessments Reduced neovascularization	/	[31]
			IGFBP3 (Phase 1 and 2)	Knockout mouse	Mouse OIR model	Reduced neuronal cell apoptosis Larger retinal avascular area	/	[32,33]
			Jb3 (Phase 2)	Subcutaneous injection	Mouse OIR model	Less neovascular tufts formation	/	[34]
Epo	↓	↑	/	/	/	/	/	/
HIF-1	↓	↑	DMOG (Phase 1)	Intraperitoneal injection	Mouse OIR model	Prevented vessel loss and vessel tufts formation	/	[35]
			PHD2 (Phase 1 and 2)	Knockout mouse	Mouse OIR model		/	[36]
			RTP801 (Phase 1 and 2)	Knockout mouse	Mouse OIR model	Induced transcription of HIF-1 in phase 2 Reduced neovascular tufts and lower apoptosis	/	[37]
NO	↓	↑	l-NA (Phase 2)	Intraperitoneal injection	Rat OIR model	Reduced avascular zone and neovascular tufts	/	[38]
			l-NNA (Phase 2)	Intraperitoneal injection	Mouse OIR model		/	[39]
			AG (Phase 2)	Intravitreal injection	Mouse OIR model		/	[40]
Adenosine	↓	↑	/	/	/	/	/	/
β-AR	?	↑	Propranolol (Phase 2)	Subcutaneous injection	Mouse OIR model	Reduced neovascularization Reduced VEGF expression	/	[41]
				Topical administration	Mouse OIR model		/	[42]
			Atenolol (Phase 2)	Subcutaneous injection	Mouse OIR model	Reduced avascular zone and neovascular tufts	/	[43]
			ICI 118,551 (Phase 2)				/
			SR59230A (Phase 2)				/
Other angiogenic agents	?	↑	Dexamethasone (Phase 2)	Subcutaneous injection	Mouse OIR model	Suppressed neovascular formation	Steroid has a higher risk of severe ROP and fungal sepsis development	[44]
			Anecortave acetate (Phase 2)	Intravitreal injection	Rat OIR model			[45]
			Degulin (Phase 2)	Intravitreal injection	Mouse OIR model	Regulated HIF-1α suppression	/	[46]
			YC-1 (Phase 2)	Intravitreal injection	Mouse OIR model		/	[47]
			β-lapachone (Phase 2)	Intravitreal injection	Mouse OIR model		/	[48]
			16K HPRL (Phase 2)	Intravitreal injection	Mouse OIR model	Mediated endothelial cell proliferation	/	[49]
			12-LOX (Phase 2)	Intraperitoneal injection	Mouse OIR model		/	[50]
			TMP (Phase 2)	Intraperitoneal injection	Mouse OIR model	Prevented neovascular formation	/	[51]
			K5 (Phase 2)	Intravitreal injection	Rat OIR model		/	[52]
			MEF2C (Phase 1 and 2)	Knockout mouse	Mouse OIR model		/	[53]

Abbreviations: Short hairpin RNA linked VEGF (VEGFA shRNA), kinase insert domain-containing receptors (KDR), recombinant human IGF-1 (rhIGF-1), IGF binding protein (IGFBP), dimethyloxalylglycine (DMOG), prolyl hydroxylase (PHD), nitric oxide (NO), N-nitro-l-arginine (L-NA), N G-nitro-l-arginine (L-NNA), aminoguanidine (AG), N-terminal fragment of human prolactin (16K HPRL), 12-lipoxygenase (12-LOX), tetramethylpyrazine (TMP), plasminogen kringle (K5), myocyte enhancer factor 2 C (MEF2C). ↑ = upregulated; ↓ = downregulated; ? = unknown.