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ing is consistent with a previously published study, demonstrating increased endothelial injury in human skin biopsies during aGvHD.10 Additionally, a series of clinical studies have collected supporting evidence on increased endothelial dysfunction during aGvHD, such as high numbers of circulating EC40-43 and elevated serum levels of the endothelial stress markers ST2, von Willebrand factor, angiopoietin 2 and thrombomodulin.31,44-46
We have previously shown that aGvHD is associated with increased angiogenesis in target organs.8,47 In the cur- rent study, we used light sheet fluorescence microscopy to demonstrate that target organ aGvHD is associated with vascular structural changes in terms of higher branching levels and larger diameter of the vasculature. Taking into account the available evidence from our previous studies as well as the experiments from this manuscript, it becomes clear that vascular destruction as well as patho- logical angiogenesis occur in parallel in the early phase during aGvHD in target organs. These processes finally
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result in restructuring of the vasculature as visualized and quantified in Figure 4. Interestingly, increased branching levels of vasculature were first reported during pathologi- cal angiogenesis in malignant tumors.48 This finding led to the concept of ‘vascular normalization’ to improve anti- tumor therapies.49 However, the significance of pathologi- cal vascular organization with increased branching level for the pathophysiology of aGvHD and possible therapeu- tic implications remains to be determined.
We found that the expression of tight junction- and adherence junction proteins were reduced during aGVHD, leading to increased vascular permeability in aGvHD target organs after allo-HSCT. The role of tight junction- and adherence junction proteins for vascular barrier maintenance50-52 as well as leukocyte transmigra- tion53,54 has been described previously. Additionally, the promotion of the adherence junction protein VE-cadherin in tumor vasculature increased T-cell infiltration into the tumor.55 These findings may open a new window for
Figure 7. In vivo treatment of acute graft-versus-host disease (aGvHD) and steroid-refractory-aGvHD with sildenafil. (A to G) Treatment of aGvHD with 10 mg/kg/d sildenafil after experimental allogeneic hematopoietic stem cell transplantation (allo-HSCT) at day+15 after experimental allo-HSCT in the radiation based B6→BALB/c model. (A) Survival analysis and (B) clinical aGvHD manifestations of sildenafil (sil) treated allo-HSCT recipients with aGvHD versus control substance phosphate buffered saline/dimethylsulfoxide (PBS/DMSO, control [ctr]) treated allo-HSCT recipients with aGvHD. Histopathological assessment of aGvHD manifes- tations in (C) liver and (D) colon in sildenafil versus control substance treated allo-HSCT recipients at day+15. Flow cytometry quantification of (E) major histocom- patibility complex I (MHCI) and MHCII expression and (F) CD80 and CD86 expression of isolated liver sinusoidal endothelial cells of sildenafil versus control substance treated allo-HSCT recipients at day+15. (G to L) Treatment with 10 mg/kg/d sildenafil in a murine model of SR-aGvHD at day+15 after experimental allo-HSCT in the radiation based B6→BALB/c model. (continued on next page.)
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haematologica | 2021; 106(8)