A critical role for both CD40 and VLA5 in angiotensin II-mediated thrombosis and inflammation.

Abstract

Angiotensin II (Ang-II)-induced hypertension is associated with accelerated thrombus formation in arterioles and leukocyte recruitment in venules. The mechanisms that underlie the prothrombotic and proinflammatory responses to chronic Ang-II administration remain poorly understood. We evaluated the role of CD40/CD40 ligand (CD40L) signaling in Ang-II-mediated microvascular responses and assessed whether and how soluble CD40L (sCD40L) contributes to this response. Intravital video microscopy was performed to analyze leukocyte recruitment and dihydrorhodamine-123 oxidation in postcapillary venules. Thrombus formation in cremaster muscle arterioles was induced by using the light/dye endothelial cell injury model. Wild-type (WT), CD40-/-, and CD40L-/- mice received Ang-II for 14 d via osmotic minipumps. Some mice were treated with either recombinant sCD40L or the VLA5 (very late antigen 5; α5β1) antagonist, ATN-161. Our results demonstrate that CD40-/-, CD40L-/-, and WT mice that were treated with ATN-161 were protected against the thrombotic and inflammatory effects of Ang-II infusion. Infusion of sCD40L into CD40-/- or CD40L-/- mice restored the prothrombotic effect of Ang-II infusion. Mice that were treated with ATN-161 and infused with sCD40L were protected against accelerated thrombosis. Collectively, these novel findings suggest that the mechanisms that underlie Ang-II-dependent thrombotic and inflammatory responses link to the signaling of CD40L via both CD40 and VLA5.-Senchenkova, E. Y., Russell, J., Vital, S. A., Yildirim, A., Orr, A. W., Granger, D. N., Gavins, F. N. E. A critical role for both CD40 and VLA5 in angiotensin II-mediated thrombosis and inflammation.

• Authors: Elena Y Senchenkova, Janice Russell, Shantel A Vital, Alper Yildirim, A Wayne Orr, D Neil Granger, Felicity N E Gavins
• Journal: FASEB journal : official publication of the Federation of American Societies for Experimental Biology (FASEB J) Vol. 32 Issue 6 Pg. 3448-3456 (06 2018) ISSN: 1530-6860 [Electronic] United States
• PMID: 29452567 (Publication Type: Journal Article)

Chemical References

• CD40 Antigens
• Integrin alpha5beta1
• Angiotensin II
• CD40 Ligand

Topics

• Angiotensin II (genetics, metabolism)
• Animals
• CD40 Antigens (genetics, metabolism)
• CD40 Ligand (genetics, metabolism)
• Humans
• Inflammation (genetics, metabolism, pathology)
• Integrin alpha5beta1 (genetics, metabolism)
• Male
• Mice
• Mice, Knockout
• Signal Transduction
• Thrombosis (genetics, metabolism, pathology)