Anti-Angiogenic Alternative and Complementary Medicines for the Treatment of Endometriosis: A Review of Potential Molecular Mechanisms

Table 2

Natural product inhibitors of angiogenesis for endometriosis.

Natural compounds	Molecular targets/mechanisms		Major targets		Type	Reference
	Anti-angiogenesis mechanisms	Others mechanisms	Anti-angiogenesis targets	Others associated Targets
Epigallocatechin gallate (EGCG)/Pro-Epigallocatechin gallate (pro-EGCG)	Inhibited VEGFC/VEGFR2 signaling pathways	Reduced lesion size; Inhibited cellular oxidation; Prevented free radical damage to cells; Enhanced lesion apoptosis; Inhibited MAPK/Smad signaling pathways	VEGFR2 ↓; VEGF-C↓	NF-κB ↓; E2 ↓; TGF-β1 ↓	Endometrial and endometriotic stromal cells/; Mouse model	[71–76]
Resveratrol	Reduced micro-vessel density (MVD)	Anti-oxidative properties; Anti-inflammatory; Enhanced apoptosis in endometriotic Stromal Cells; Inhibited vascularization and cell proliferation	VEGF↓; TNF-ɑ↓	MCP-1 ↓; MMP-2 ↓; MMP-9 ↓; IL-6 ↓; IL-8 ↓; HMGCR ↓; ESR1↓; CA125 ↓	Endometriotic stromal cells (ESCs)/Rat model/Clinical trials	[77–85]
Palmitoylethanolamide	Reduced VEGF	Inhibited development of endometriotic lesions; Reduced peroxynitrite formation	VEGF↓; NGF↓	VCAM-1↓; MMP-9↓; poly-ADP↓; Ik-Bɑ↓; NF-κB↓	Rat model	[86]
Achillea biebersteinii Afan	Reduced peritoneal fluid levels of TNF-α, VEGF	Reduced endometriotic volumes	VEGF↓; TNF-ɑ↓	IL-6↓	Sprague Dawley rats model	[87]
Viburnum opulus L.	Reduced VEGF	Reduced endometriotic volumes	VEGF↓; TNF-ɑ↓,	IL-6↓	Rat model	[88]
Genistein; (Flavonoids)	Regulated angiogenesis	Regulated inflammation; Reduced the expression of estrogen receptor α; Increased the expression of estrogen receptor β	VEGF↓	HIF-1α↓	Murine model	[91, 92]
Xanthohumol; (prenylated flavonoid)	Suppressed vascularization in endometriotic lesions	Inhibited the development of endometriotic lesions; Anti-proliferative Anti-inflammatory	MVD ↓	Phosphoinositide 3-kinase protein↓	BALB/c mouse model	[93]
Sea buckthorn and St. John's wort	Reduced the level VEGF in peritoneal fluids	Inhibited the development of endometriotic lesions	TNF-α↓; VEGF↓	IL-6↓	Rat model	[94]
Naringenin; (Flavonoids)	Regulated VEGF/KDR signaling pathway in human endothelial cells	Inhibited proliferation; Increased apoptosis; Regulated MAPK and AKT signal transduction pathways in human endometriosis cell lines	VEGF↓; KDR(VEGFR2) ↓	PI3K↓; MAPK↓	In (VK2/E6E7 and End1/E6E7)human endometriosis cell lines/; Human endothelial cells	[95, 96]

CA125: carcinoembryonic antigen; ESR1: estrogen receptor-ɑ; HMGCR: 3-hydroxy-3-methylglutaryl-CoA reductase; IL-6: interleukin (IL)-6; MAPK: mitogen-activated protein kinase; MCP-1: monocyte chemoattractant protein-1; MMP-2: matrix metalloproteinases-2; MMP-9: matrix metalloproteinases-9; MVD: microvessel density; NGF: nerve growth factor; poly-ADP: lymphocyte accumulation and reduced peroxynitrite formation; TGF-β1: transforming growth factor; TNF-α: tumor necrosis factor-α.