SCD40L ‐CD40/VLA‐ 5 Signaling Contributes to AngII‐induced Thrombosis and Inflammation.

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AngII‐induced hypertension is associated with accelerated thrombus formation and leukocyte recruitment. The objective of this study was to evaluate the mechanisms underlying the prothrombogenic‐proinflammatory responses associated with chronic AngII infusion. We assessed the contribution of CD40/CD40L to these AngII‐mediated responses and whether/how the generation of soluble CD40L(sCD40L) contributes to the exacerbated thrombosis and leukocyte recruitment. Thrombus formation in mouse arterioles was induced using the light/dye injury model, while firm adhesion of leukocytes was quantified in adjacent venules. Wild type (WT), CD40‐/‐, CD40L‐/‐ , bone marrow chimeric CD40‐/‐ and CD40L‐/‐ mice (CD40‐/‐→WT or CD40L‐/‐→WT) were infused with AngII (1 µg/kg/min for 14 days) via osmotic pumps. Some WT mice and AngII infused WT mice were treated with either recombinant sCD40L, a P‐selectin blocking antibody, or a VLA5 antagonist (ATN‐161). The studies revealed that both AngII‐infused CD40‐/‐ and CD40L‐/‐ exhibited reduced leukocyte adhesion and oxidative stress in venules, and a blunted thrombosis response in arterioles. WT‐AngII mice treated with ATN‐161 were completely protected against the enhanced thrombosis and leukocyte adhesion responses to AngII, while P‐selectin immunoblockade offered only partial protection. Infusion of recombinant sCD40L in either WT, CD40‐/‐, or CD40L‐/‐ mice restored the accelerated thrombus formation elicited by AngII infusion. These findings implicate sCD40‐CD40L/VLA‐5‐dependent signaling in the prothrombotic‐proinflammatory responses elicited by chronically elevated AngII levels (Postdoctoral Fellowship from Malcolm Feist Endowment).