TABLE 2

Administration routes of pro-angiogenic therapies aimed at promoting brain revascularization in preclinical trials

Route	Procedure	Vector	Therapeutic factor	Dose	Duration of treatment	CNS disease	Ref.
Systemic	Tail vein injection/ infusion	-	rhANGPTL4	40 µg/kg	Single dose	IS	(Bouleti et al., 2013)
		-	rhVEGF₁₆₅	1 mg/kg	5 µl/min, 4 hours	IS	(Zhang ZG et al., 2000)
		-	rhVEGF₁₆₅human neural stem cells	50 µg/kg500 µl	1 µg/kg, 1hour10⁴ cells/µl, 5min	IS	(Chu K et al., 2005)
		AV transfected human mesenchymal stem cells	PlGF	10⁷ cells	Single dose	IS	(Liu H et al., 2006)
	Retro-orbital sinus	Fusogenic liposomes	Resveratrol	2 mg/kg/day	4 days	Ag	(Wiedenhoeft et al., 2019)
	Intraperito-neal	-	rhVEGF₁₆₅	8 µg/kg/day	3 days	AD	(Wang P et al., 2011)
	Intraperito-neal	-	Vitamin C	2000 mg/kg	Single dose	IS	(Chang et al., 2020)
Intracerebral	Diffusion from cortex	PLGA nanospheres	rhVEGF₁₆₅	1 µg/mouse	Single dose	AD	(Herran et al., 2013a)
		Encapsulated BHK-VEGF cells	hVEGF₁₆₅	20–30 microcapsules	Single dose	AD	(Spuch et al., 2010)
		Encapsulated BHK-VEGF cells	hVEGF₁₆₅	1microcapsule (10⁶ cells); 10-20 ng VEGF released/day	Single dose	IS	(Yano et al., 2005)
	Osmotic mini-pumps	-	rhVEGF₁₆₅	10 µg/ml	1 µl/hour, 3 days	IS	(Sun Y et al., 2003)
	Osmotic mini-pumps	IgG antibody	Anti-Nogo-A	7 mg/ml	7 days	IS	(Rust, et al., 2019b)
	Local injection	AAV	hVegf₁₆₅	5 µl (5x10⁹ TU/ml)	0.2 µl/min, 15 min	IS	(Shen F et al., 2006)
		AAVH9	hVegf₁₆₅	5 µl (2x10⁹ TU/ml)	0.2 µl/min, 15 min	IS	(Shen F et al., 2008)
		AAV	Sestrin2	10 µl (10¹⁰ TU/ml)	0.5 µl/min, 20 min	IS	(Li Y et al., 2020)
		AAV	PlGF	3x10⁹ AAV particles	2 µl × 4 injections	IS	(Gaál et al., 2013)
		AV	hbFGF	50 µl (1x10⁸ TU)	3.3 µl/min, 15 min	IS	(Watanabe et al., 2004)
		Lentivirus	miR-210	2.2 µl (2x10⁹ TU/ml)	0.2 µl/min, 15 min	N, IS	(Zeng L et al., 2014; Zeng LL et al., 2016)
		Lentivirus	miR-126	2 µl (5.6x10⁸ TU/ml)	0.2 µl/min, 10 min	IS	(Qu et al., 2019)
		Lentivirus	miR-124	0.2 µl (10⁸ TU/ml)	Single dose	AD	(Li AD et al., 2019)
		Niosomes	hVegf₁₆₅	5 µl	Single dose	N	(Gallego et al., 2020)
		PLGA microparticle	hNSCrhVEGF₁₆₅	20 µg/µl (10⁴ cells)	Single dose	IS	(Bible et al., 2012)
		hNSC	hVegf₁₆₅	2 µl (2x10⁵ cells)	Single dose	IS	(Lee et al., 2007)
		HSV-1 transfected BMSC cells	hbFGF	10 µl (1x10⁶ cells)	Single dose	IS	(Ikeda et al., 2005)
		HA hydrogel	rhVEGF₁₆₅	6 µl	Single dose	IS	(Ju et al., 2014; Nih et al., 2016)
		PEG-PPS hydrogel	iPS-NPC cells	-	Single dose	N	(Zhang J et al., 2011)
Intranasal	Neuro-olfactory pathway	-	rhVEGF₁₆₅	100 µl/day(200 µg/ml)	10 µl at a time for 18.5min, at intervals of 2min, alternating the nostrils. 3 days	IS	(Yang et al., 2009a)
		RVG29-PEG-PLGA nanoparticles	miR-124	2 drops containing miR-124 at 5 µg/ml	Every 2 days after the modeling during a week	IS	(Hao et al., 2020)

AAV, adeno-associated virus; AD, Alzheimeŕs disease; Ag, aging; ANGPTL4, angiopoietin-like 4; AV, adenovirus; BHK, baby hamster kidney cells; BMSC, bone marrow stromal cells; CNS, central nervous system; HA, hyaluronic acid; HSV-1, herpes simplex virus type 1; iPS-NPC, human induced pluripotent stem-neural progenitor cells; IS, ischemic stroke; hMSCs human mesenchymal stem cells; hNSC, human neural stem cell; N, normal; NSC, neural stem cells; PEG, poly(ethylene glycol); PLGA, poly(lactic-co-glycolic acid); PPS, poly(propylene sulfide); rh, recombinant human; TU, transducing units; VEGF, vascular endothelial growth factor.