Assessing Phenoxodiol's Capacity as a Therapeutic for Preeclampsia — ASN Events
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Assessing Phenoxodiol's Capacity as a Therapeutic for Preeclampsia (#522)

Wini Vudiniabola 1 2 , Dilara Dassanayake 1 2 , Manju Kandel 1 2 , Tuong-Vi Nguyen 1 2 , Ping Cannon 1 2 , Stephen Tong 1 2 , Lucy Bartho 1 2 , Tu'uhevaha Kaitu'u-Lino 1 2
  1. Obstetrics, Gynaecology and Newborn Health, University of Melbourne, Heidelberg, VIC, Australia
  2. Mercy Perinatal, Mercy Hospital for Women, Heidelberg, Victoria, Australia

Background 

Preeclampsia is a pregnancy disorder characterised by maternal endothelial dysfunction. This study aimed to explore whether a novel compound, phenoxodiol, can activate pro-angiogenic pathways and improve endothelial dysfunction in vitro.  

Methods 

Our team conducted a high-throughput screen and identified phenoxodiol as an activator of vascular endothelial growth factor receptor-2 (VEGFR2). We studied the effect of phenoxodiol (2µM, 4µM and 8µM) on primary human umbilical vein endothelial cells (HUVECs) treated with TNF⍺ to model maternal endothelial dysfunction and primary cytotrophoblasts isolated from placenta at term. Gene expression (ET-1, ICAM1, VCAM1, HMOX1, TXN, GCLC and PDSS1) was assessed via qRT-PCR and protein expression (sFLT1) was assessed via ELISA (n=5 per treatment). 

Results 

At 2µM, 4µM and 8µM phenoxodiol did not impact cell viability in HUVECs. TNF⍺ increased endothelial dysfunction markers ICAM1 and VCAM1 but this was not rescued by phenoxodiol treatment. Surprisingly, phenoxodiol significantly increased potent vasoconstrictor, ET-1 expression (p<0.0001) at 4µM and 8µM. 

Phenoxodiol significantly reduced TNF⍺-induced leukocyte adhesion (p<0.0001) at 2µM, 4µM and 8µM. 

We next tested whether treatment of phenoxodiol had cytoprotective benefits in HUVECs. Phenoxodiol significantly increased cytoprotective genes HMOX1 (p<0.0001) at 2µM, 4µM and 8µM and TXN (p=0.0005) at 4µM and 8µM. GCLC and PDSS1 were unchanged.  

In cytotrophoblasts treated with phenoxodiol for 24-hours or 48-hours, GCLC (p=0.0006, 24-hour; p=0.0023, 48-hour) at 2µM, 4µM and 8µM, HMOX1 (p=0.0005, 24-hours; p=0.003, 48-hours) at 4µM and 8µM and TXN (p=0.0002, 24-hours; p=0.007, 48-hours) at 4µM and 8µM were significantly increased. PDSS1 was unchanged.  

In the presence of high sFLT1, phenoxodiol activated VEGFR2. Phenoxodiol also significantly reduced sFLT1 secretion from cytotrophoblasts (p=0.025), but not HUVECs. 

Conclusion 

This study showed that phenoxodiol can activate VEGFR2, enhance cytoprotective markers and have some positive effects on endothelial dysfunction. With further study, it could be considered as a potential therapeutic for preeclampsia.