Uncovering a Sex-Specific cAMP Landscape in Vascular Smooth Muscle
- 1University of California Davis
Abstract
The second messenger, cyclic adenosine monophosphate (cAMP), plays a crucial role in regulating cellular function, including in vascular smooth muscle (VSM). While extensive research has focused on the compartmentalization of cAMP signaling in various cell types, the influence of biological sex on distinct cAMP pools and their functional implications in the VSM remains largely unexplored. To address this knowledge gap, we employed a multiscale experimental approach spanning targeted cAMP biosensors, wire myography, live-cell calcium imaging, proximity ligation assays, and in vivo ultrasound imaging. Our findings reveal a sex-specific distribution of cAMP signaling domains, with the cAMP pool selectively present in the SR of females but not males in the VSM. Ovariectomy abolished this sexual dimorphism, with SR cAMP pools disappearing in ovx females, mirroring the pattern observed in male cells. Males and ovx female VSM exhibited a significantly stronger RyR-PDE3/PDE4 association than sham females, suggesting that ovarian hormone-dependent sequestration of phosphodiesterases away from the SR licenses cAMP signaling in this compartment in female cells. Functionally, this sexually dimorphic cAMP compartmentalization correlates with smaller Ca2+ spark amplitude, reduced isoproterenol-induced relaxation, and higher pulse wave velocity in male and ovx compared to female VSM/vessels/mice. Together, these findings establish biological sex as a fundamental determinant of subcellular cAMP organization in VSM, with implications for understanding sex differences in vascular function and cardiovascular disease.
Related
- Genetic dissection of cell type–specific congenital heart disease variants reveals ETS1 control of vascular smooth muscle cell fate
- Smooth muscle DDIT4 exacerbates vascular remodeling in atherosclerosis and vascular injury by impairing PDC activity
- An in vitro System for Studying Osteochondrogenic Differentiation of Smooth Muscle Cells and Modeling Intimal Vascular Calcification
- Myf5 Progenitors Define the Lineage Identity of Somitic Vascular Smooth Muscle Cells.
- Vascular Smooth Muscle Cell Plasticity in Atherosclerosis: From Macrophage-like Transdifferentiation to Therapeutic Targeting
BibTeX
@misc{silva2026uncovering,
title = {{Uncovering a Sex-Specific cAMP Landscape in Vascular Smooth Muscle}},
author = {E. Pereira da Silva and I. Alves and H. Voorhees and P. Sirish and N. Daghbouche Rubio and M. Martin Aragon Baudel and Y. Xiang and M. F. Navedo and M. Nieves-Cintron},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.11.751051},
url = {https://www.biorxiv.org/content/10.64898/2026.09.11.751051v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Uncovering a Sex-Specific cAMP Landscape in Vascular Smooth Muscle
AU - E. Pereira da Silva
AU - I. Alves
AU - H. Voorhees
AU - P. Sirish
AU - N. Daghbouche Rubio
AU - M. Martin Aragon Baudel
AU - Y. Xiang
AU - M. F. Navedo
AU - M. Nieves-Cintron
PY - 2026
DA - 2026/09/11
PB - bioRxiv
DO - 10.64898/2026.09.11.751051
UR - https://www.biorxiv.org/content/10.64898/2026.09.11.751051v1
AB - The second messenger, cyclic adenosine monophosphate (cAMP), plays a crucial role in regulating cellular function, including in vascular smooth muscle (VSM). While extensive research has focused on the compartmentalization of cAMP signaling in various cell types, the influence of biological sex on distinct cAMP pools and their functional implications in the VSM remains largely unexplored. To address this knowledge gap, we employed a multiscale experimental approach spanning targeted cAMP biosensors, wire myography, live-cell calcium imaging, proximity ligation assays, and in vivo ultrasound imaging. Our findings reveal a sex-specific distribution of cAMP signaling domains, with the cAMP pool selectively present in the SR of females but not males in the VSM. Ovariectomy abolished this sexual dimorphism, with SR cAMP pools disappearing in ovx females, mirroring the pattern observed in male cells. Males and ovx female VSM exhibited a significantly stronger RyR-PDE3/PDE4 association than sham females, suggesting that ovarian hormone-dependent sequestration of phosphodiesterases away from the SR licenses cAMP signaling in this compartment in female cells. Functionally, this sexually dimorphic cAMP compartmentalization correlates with smaller Ca2+ spark amplitude, reduced isoproterenol-induced relaxation, and higher pulse wave velocity in male and ovx compared to female VSM/vessels/mice. Together, these findings establish biological sex as a fundamental determinant of subcellular cAMP organization in VSM, with implications for understanding sex differences in vascular function and cardiovascular disease.
ER -