Table 1.

Signaling molecules in macrophage-mediated vascular repair and neovascularization.

Functions	Signaling Molecules	Effects on Macrophages	Phenotypes upon Injury	Ref.
Chemotaxis and cell recruitment	AGE-RAGE	Reduce macrophage infiltration and interaction with EC	RAGE KO or overexpression of reduced AGE enhance vascular repair in diabetic mice upon HLI	[8]
	CCL2-CCR2	Recruitment of proangiogenic monocytes/macrophages	CCR2 KO impairs recovery of blood flow recovery, vessel size, and active foot movement in HLI mice	[9,10]
	CXCL10-CXCR3	Regulate leucocyte infiltration	CXCR3 KO reduces VEGF production, angiogenesis, blood perfusion, and capillary density	[11]
	PGC-1α-SPP1	Recruit macrophage and upregulate CCL2 production	PGC-1α overexpression improves angiogenesis and blood flow recovery in adult, aged, diabetic mice; SPP1 KO induces immature capillarization and blunted arterialization	[12]
	SEMA3A/VEGF-NRP-1	Recruit NRP-1+ macrophage	NRP-1 deficient macrophage fail to enter retinal and reduce neovascularization in OIR mice	[13]
	SERCA 2	Regulated VEGF production and adhesion to EC	Mediated immune cells infiltration and adhesion via ERO1 and VCAM-1 expression in EC	[14]
	VASP	Form complex with CCR2, suppress macrophage differentiation via STAT signaling	KO increase blood flow recovery, angiogenesis, arteriogenesis, and leukocyte infiltration upon HLI	[15]
Angiogenesis	ANG/TIE2	Upregulate HIF signaling via repressing Phd2 and M2 polarization	ANG or TIE2 overexpression increases vessel density, reduced ischemic necrosis in HLI mice	[16,17,18]
	DLL1-NOTCH	Promote differentiation from Ly6Chi monocyte, enhanced phagocytic capacity and anti-inflammatory phenotype	Heterozygous Dll1 mutant prevents arteriogenesis, blood perfusion, and tissue recovery in HLI mice	[19,20]
	HIF	HIF-1α KO reduced macrophage migration and suppressed pro-inflammatory phenotype	KO impairs ruptured vessel repair, angiogenesis, and tissue repair	[21]
	IL-8	M2 polarization	Blockade of IL-8 suppresses angiogenesis	[22,23]
	MiR93/IRF9/IRG1/itaconic acid	MiR93-mediated suppression of IRF9/IRG1/itaconic acid induces M2 polarization	MiR93 overexpression promotes angiogenesis, arteriogenesis, and blood perfusion	[24]
	MMP-9	Secreted by M2 macrophage	KO reduces capillary branching	[25]
	PR39 peptide	Inhibited the degradation of HIF-1 α	Promote angiogenesis	[26]
	VEGF-VEGFR	Activate NOTCH signaling, induce maturation and M2 polarization	Promote EC migration, proliferation and angiogenesis	[19,27]

Abbreviation in the table: HLI, hindlimb ischemia; OIR, oxygen-induced retinopathy.