A critical role for both CD40 and VLA5 in angiotensin Il–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.

Novel Role of T Cells and IL-6 (Interleukin-6) in Angiotensin II–Induced Microvascular Dysfunction

“…It is important to note that our findings here are not related to elevated blood pressure per se, but rather Ang-II-mediated effects on thrombus formation. Previously we published data in an alternative model of HTN (deoxycorticosterone acetate [DOCA] salt-induced HTN), which had no effect on thrombus formation and CD40 −/− mice implanted with AngII-loaded pumps exhibit protection against Ang-II-mediated thrombosis but remain hypertensive, 34 further supporting our findings here that elevated blood pressure per se is mediating the effects.…”

“…Interestingly, we found here that chronically elevated levels of Ang-II resulted in not only increased platelet counts, but resulted in heightened numbers of immature platelets (or reticulated platelets). 34,35 Rag-1 −/− mice however were protected against this increase and adoptive transfer of T cells isolated from WT mice and transferred into Rag-1 −/− recipients restored increased levels of immature platelets, suggesting that a reciprocal crosstalk exists between these two cell types: T cells and platelets.…”

“…Several cytokines (e.g. TNFα, IFNγ, IL-1β, IL-6) 31,34,37 are known to contribute to the thrombo-inflammatory responses associated with acute and chronic inflammation, with IL-6 being considered a clinical biomarker of CVD. 38,39 The normal range of IL-6 in plasma is about 5-7 pg/ml in human population 37 and its secretion is upregulated in response to Ang-II, oxidative stress and vascular injury, 19,[38][39][40] which concurs with increased IL-6 levels in these studies.…”

Effects of Shift Work on the Carotid Artery and Cerebral Blood Flow of Spontaneously Hypertensive Rats and Wistar-Kyoto Rats

“…These effects lead to damages in the endothelial cells of the carotid artery and cause the formation of arterial thrombosis [76][77][78][79][80][81][82][83][84] . Thirdly, increased blood pressure induced by SW may also cause the formation of arterial thrombosis [85,86] . Therefore, the development of carotid arterial thrombosis is a result of the widespread adverse effects of SW.…”

The vascular nature of COVID-19

“…5 It was stated that the viral infection invaded the endothelium of the systemic vascular system damaging the Angiotensin Converting Enzyme two (ACE2) receptors thereby releasing angiotensin II and triggering microthrombus development and inflammation at the same moment. 6 ACE2 is present in most organs: ACE2 is attached to the cell membrane of mainly arterial and venous endothelial cells, lung type II alveolar cells, enterocytes of the small intestine, and arterial smooth muscle cells in most organs.…”