Sex differences in RAMP1/RAMP2 expression in the human middle meningeal artery match functional response to CGRP

CGRP induces vasodilation after binding to the CGRP receptor (CLR-RAMP1), but can activate the adrenomedullin receptor (CLR-RAMP2) as well. Previously, age-dependent sex differences were observed for CGRP-induced relaxation of human middle meningeal arteries1. In addition, RAMP1 and RAMP2 mRNA expression was highly variable between patients2. The current study aims to investigate whether RAMP1 and RAMP2 expression differs between men and women and varies throughout life.

RNA was isolated from homogenized human middle meningeal arteries (14 F, 12 M, age 51±3 years) and qPCR was performed for RAMP1 and RAMP2 mRNA expression. The ratio between RAMP1 and RAMP2 expression with increasing age was investigated for men and women separately.

The RAMP1/RAMP2 ratio significantly decreases with age in men, while a positive trend can be observed for women. These findings match the pattern of maximum relaxation to CGRP as observed in a previous study1, with a significant decrease with age in men and a trend for increased maximum relaxation with age in women.

The current study suggests that the maximum effect of CGRP-induced relaxation of human middle meningeal arteries matches the ratio of RAMP1/RAMP2 expression, and changes in a sex-dependent manner with increasing age. Interestingly, migraine is generally most prevalent in pre-menopausal women. Here, these young women show a relatively high RAMP2 and low RAMP1 expression, suggesting predominance of the adrenomedullin receptor over the canonical CGRP receptor in this population. Possibly, increased exposure of CGRP in young women results in downregulation of RAMP1. Future research should investigate whether RAMP1 and RAMP2 expression is altered in migraine patients.

References

1) de Vries T., Boucherie D. M., et al. 2024. Cephalalgia In Press

2) de Vries T., Schutter D. et al. 2023. P200 European Headache Congress 2023, Barcelona, Spain.