Mast Cells and Vascular Endothelial Growth Factor Contribute to Pelvic Tactile Allodynia in a Non-invasive Mouse Model of Endometriosis

Endometriosis (EM) impacts ~4 million women in the US. EM lesions are infiltrated with mast cells (MCs) and have elevated vascular endothelial growth factor (VEGF). To test the hypothesis that MC and VEGF drive endometriosis-associated pelvic pain, we assessed therapeutic agents on pelvic tactile allodynia in a mouse model of EM. C57BL/6J donor mice (6-weeks old) received a subcutaneous injection of estradiol benzoate (10µg), and 4 days later, each uterine horn was excised and placed in Hank’s Balanced Salt Solution (HBSS) and minced. Recipient mice received an intraperitoneal injection of either HBSS (500µl; “Shams”) or HBSS+ donor mice minced uterine horn (500µl; “EM mice”). To assess pelvic tactile allodynia in recipient/EM mice, von Frey filaments were applied suprapubically from day 0 to 28. We determined the effect of the MC stabilizer β-nicotinamide mononucleotide (NMN; 150mg/kg) or the VEGFR2 inhibitor SKLB1002 (SB; 100mg/kg) on mechanical hypersensitivity. In Shams, neither saline, NMN, nor SB changed mechanical thresholds. In EM mice, NMN and SB but not saline reversed hypersensitivity (p<0.05). Next, in mice without EM, we demonstrated that intrauterine VEGF dose-dependently induces pelvic tactile allodynia. Thus, we investigated the effect of intrauterine NMN (50 mg/kg) on VEGF-induced pelvic tactile allodynia at day 28. Mechanical thresholds remain unchanged in controls (0.9% saline) receiving intrauterine saline or NMN. However, NMN but not saline reversed VEGF-induced hypersensitivity (p<0.05). Taken together, 1) stabilizing MCs or inhibiting VEGFR2 alleviates pelvic tactile allodynia, and 2) intrauterine VEGF elicits pelvic tactile allodynia that is reversible with blunting of MC activity. Acknowledgment: NIDDK K01DK114395-06 (PI: Kenny Roman, PhD) and the University of Pittsburgh Start-Up funds (PI: Kenny Roman, PhD, and Co-PI: Bradley K. Taylor, PhD).