Pharmacological effects of nebivolol on endothelial response in a preeclampsia in vitro model

Preeclampsia (PE) is a pregnancy-specific hypertensive disorder characterized by systemic endothelial dysfunction and a profound anti-angiogenic state driven by elevated soluble fms-like tyrosine kinase-1 (sFlt-1). While the third-generation β₁-AR nebivolol promotes vasodilation partially via receptor β₃-AR activation, whether its protective effects can reverse the complex anti-angiogenic and hypoxic stress of PE remains unclear.

This study aimed to determine the functional and molecular effects of nebivolol in a PE-like endothelial microenvironment and to understand the specific contribution of β₃-AR.

Endothelial cells exposed to chemical hypoxia and 10% plasma from women with early-onset PE were treated with nebivolol, the selective β₃-AR agonist CL316,243, or the β₃-AR antagonist L-748,337. We quantified sFlt-1 secretion, evaluated the transcription of key angiogenic, vasoactive, and cytoprotective genes, and assessed cell migration using migration and transwell assays.

Nebivolol selectively modulated specific components of the PE phenotype, reducing sFlt-1 secretion, downregulating VEGFR2 and EDN1, and upregulating HMOX1. Conversely, it significantly inhibited endothelial cell migration. Crucially, selective β₃-AR activation via CL316,243 failed to mirror these integrated responses, and β₃-AR antagonism did not reverse nebivolol's actions.

We conclude that nebivolol's protective effects in a PE-like environment do not depend primarily on β₃-AR activation, but rather reflect a broader, pleiotropic vascular pharmacological profile. Translating these results clinically suggests that targeting single-receptor pathways may be insufficient in the complex environment of PE, positioning multi-target agents like nebivolol as candidates for modulating endothelial dysfunction in gestational hypertensive disorders.