Basic fibroblast growth factor induces proliferation and collagen production by fibroblasts derived from the bovine corpus luteum

Authors

Corrine F. Monaco, University of Nebraska Medical Center
Michele R. Plewes, University of Nebraska Medical Center, US Department of Veterans Affairs-Nebraska Western Iowa Healthcare SystemFollow
Emilia Przygrodzka, University of Nebraska Medical Center
Jitu W. George, University of Nebraska Medical Center, US Department of Veterans Affairs-Nebraska Western Iowa Healthcare System
Fang Qiu, University of Nebraska Medical CenterFollow
Peng Xiao, University of Nebraska Medical CenterFollow
Jennifer R. Wood, University of Nebraska—LincolnFollow
Andrea S. Cupp, University of Nebraska—LincolnFollow
John S. Davis, University of Nebraska Medical CenterFollow

Document Type

Article

Date of this Version

6-5-2023

Citation

Biology of Reproduction, 2023, 109(3), 367–380. https://doi.org/10.1093/biolre/ioad065

Comments

This work is written by (a) US Government employee(s) and is in the public domain in the US.

Abstract

Cyclic regression of the ovarian corpus luteum, the endocrine gland responsible for progesterone production, involves rapid matrix remodeling. Despite fibroblasts in other systems being known for producing and maintaining extracellular matrix, little is known about fibroblasts in the functional or regressing corpus luteum. Vast transcriptomic changes occur in the regressing corpus luteum, among which are reduced levels of vascular endothelial growth factor A (VEGFA) and increased expression of fibroblast growth factor 2 (FGF2) after 4 and 12 h of induced regression, when progesterone is declining and the microvasculature is destabilizing. We hypothesized that FGF2 activates luteal fibroblasts. Analysis of transcriptomic changes during induced luteal regression revealed elevations in markers of fibroblast activation and fibrosis, including fibroblast activation protein (FAP), serpin family E member 1 (SERPINE1), and secreted phosphoprotein 1 (SPP1). To test our hypothesis, we treated bovine luteal fibroblasts with FGF2 to measure downstream signaling, type 1 collagen production, and proliferation. We observed rapid and robust phosphorylation of various signaling pathways involved in proliferation, such as ERK, AKT, and STAT1. From our longer-term treatments, we determined that FGF2 has a concentration-dependent collagen-inducing effect, and that FGF2 acts as a mitogen for luteal fibroblasts. FGF2- induced proliferation was greatly blunted by inhibition of AKT or STAT1 signaling. Our results suggest that luteal fibroblasts are responsive to factors that are released by the regressing bovine corpus luteum, an insight into the contribution of fibroblasts to the microenvironment in the regressing corpus luteum.