Faculty Collaboration Database

Anti-TNF, pan-JAK, and JAK1-selective inhibition differentially alter mechanisms of flow-mediated dilation in human microvessels. Am J Physiol Heart Circ Physiol 2026 Sep 01;331(3):H894-H899

Date

08/09/2026

Pubmed ID

42552281

DOI

10.1152/ajpheart.00517.2026

Scopus ID

2-s2.0-105048118874 (requires institutional sign-in at Scopus site)

Abstract

Patients with chronic inflammatory disorders, including inflammatory bowel disease (IBD), carry an increased risk of cardiovascular disease. The 2022 ORAL Surveillance study reported that the pan-selective Janus kinase inhibitor (JAKi) tofacitinib was associated with increased risk of major adverse cardiovascular events (MACE) among patients with rheumatoid arthritis compared with antitumor necrosis factor (anti-TNF) therapy. This prompted guideline changes regarding the use of all JAKis, including upadacitinib, a JAK1-selective drug approved for use in chronic inflammatory conditions, including IBD. However, the mechanism underlying JAKi-related MACE outcomes and the significance of JAK selectivity relative to TNF inhibition remain unclear. Microvascular dysfunction (MVD) is a predictor of MACE. Flow-mediated dilation (FMD) is a measure of MVD. Using an established ex vivo model of resistance arterioles isolated from adipose tissue, we performed the first mechanistic comparison of antitumor necrosis factor (anti-TNF; infliximab), pan-JAK inhibitor (tofacitinib), and JAK1-selective (upadacitinib) therapies on human microvascular endothelial function. Arterioles were obtained from low-cardiovascular-risk subjects of both sexes. Isolated microvessels were incubated with drugs of interest. Flow-mediated dilation (FMD), an assessment of MVD, was measured before and after nitric oxide (NO) synthase inhibition or hydrogen peroxide (H₂O₂) scavenging. No therapy statistically altered FMD magnitude, yet underlying mechanisms differed. Control and infliximab-treated vessels maintained physiologic NO-mediated dilation. Tofacitinib induced a shift toward pathologic H₂O₂-mediated dilation. Upadacitinib impaired NO-dependent dilation without evidence of compensatory H₂O₂ signaling. In summary, anti-TNF therapy and selective versus nonselective JAKi differentially modulate endothelial mechanisms of vasodilation, suggesting unique microvascular phenotypes with potential implications for cardiovascular risk.NEW & NOTEWORTHY This is the first ex vivo mechanistic comparison of antitumor necrosis factor therapy (infliximab) and selective (upadacitinib) versus nonselective (tofacitinib) Janus kinase inhibition in human microvessels. Flow-mediated dilation showed no statistical differences; however, the mechanisms driving endothelial dilation varied. We report a shift from nitric oxide- to hydrogen peroxide-mediated dilation with tofacitinib, a distinct phenotype with upadacitinib, and nitric oxide-dependent dilation with infliximab, suggesting differential effects of IBD therapies on microvascular endothelial physiology.

Author List

Kleynerman Roels A, Birch EC, Nishijima Y, Hader SN, Beyer AM, Sinh PC

Author

Andreas M. Beyer PhD Professor in the Medicine department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Adult
Female
Heterocyclic Compounds, 3-Ring
Humans
Infliximab
Janus Kinase 1
Janus Kinase Inhibitors
Male
Microvessels
Middle Aged
Nitric Oxide
Piperidines
Pyrimidines
Tumor Necrosis Factor-alpha
Vasodilation