Mesua ferrea L. extract Attenuates Angiogenesis Through HIF-1α and WNT Mediated Blockage of VEGF/Angiopoietin Axis

Objectives The current study investigated angiogenesis-arresting attributes of Mesua ferrea oleo-gum resin extract and its underlying molecular mechanisms. Methods Series of in vitro , ex vivo and in vivo models were used to assess anti-angiogenic properties. Results MTT cell viability experiments showed that oleo-gum resin extract induced moderate cytotoxicity towards EA.hy926 cells (IC 50 = 42 µg/mL). Extract-treated cells showed significant reduction in invasion, migration, and tube formation potential. At the protein level, down-regulation in expression of angiopoietin-1 and -2, Tie-2, MMP-1 and -9, VEGF-A, and VEGFR2 pro-angiogenic proteins was observed in extract-treated EA.hy926 cells. Signalling array data indicated a marked down-regulation of transcription factors, i.e., HIF-1α and WNT (−3.68 ± 5.74 and −6.24 ± 6.50 fold-change). Furthermore, extract treatment diminished vessel-sprouting in in vitro 3D spheroids, ex vivo rat aorta ring, and in vivo chick embryo chorioallantoic membrane models. Treatment with extract significantly reduced intracellular ROS and caspases-8 and -9 levels. GC-MS and HPLC analyses of extract indicated the presence of (+)-α-longipinene, isoledene, cedrene and α-elemene. ADMET prediction of detected compounds revealed good intestinal absorption (> 90%) and skin permeability (log Kp < −2.5), making the extract a suitable candidate for the treatment of angiogenesis-associated intestinal and skin disorders. Conclusion Overall, these findings suggest that Mesua ferrea extract exhibits anti-angiogenic properties by down-regulating the VEGF/angiopoietin axis, warranting further investigations in treating angiogenesis-associated diseases.