Endoglin Deficiency Impairs Stroke Recovery

Abstract

Background and Purpose Endoglin (ENG) deficiency causes hereditary hemorrhagic telangiectasia-1 (HHT1) and impairs myocardial repair. Pulmonary arteriovenous malformations (AVM) in HHT1 patients are associated with a high incidence of paradoxical embolism in the cerebral circulation and ischemic brain injury. We hypothesized that ENG deficiency impairs stroke recovery. Methods Eng heterozygous (Eng+/−) and wild-type (WT) mice underwent permanent distal middle cerebral artery occlusion (pMCAO). Pial collateral vessels were quantified before pMCAO. Infarct/atrophic volume, vascular density and macrophages were quantified in various days after pMCAO; and behavioral function was assessed using corner and adhesive removal tests on days 3, 15, 30 and 60 after pMCAO. The association between ENG 207G>A polymorphism and brain AVM rupture and surgery outcome was analyzed using logistic regression analysis in 256 ruptured and 157 unruptured patients. Results After pMCAO, Eng+/− mice showed larger infarct/atrophic volumes at all time points (P<0.05), and worse behavior performance (p<0.05) at 15, 30 and 60 days compared to WT mice. Eng+/− mice had fewer macrophages on day 3 (P=0.009) and more macrophages on day 60 (P=0.02) in the peri-infarct region. Although Eng+/− and WT mice had similar numbers of pial collateral vessels before pMCAO, Eng+/− mice had lower vascular density in the peri-infarct region (p=0.05) on day 60 after pMCAO. In humans, ENG 207A allele has been associated with worse outcomes after AVM rupture or surgery of unruptured AVM patients. Conclusions ENG deficiency impairs brain injury recovery. Reduced angiogenesis, impaired macrophage homing, and delayed inflammation resolution could be the underlying mechanism.

Persistent infiltration and pro-inflammatory differentiation of monocytes cause unresolved inflammation in brain arteriovenous malformation

“…4b & c ). These data confirm previous observations that the ability of Eng -deficient monocyte homing to angiogenic/injury tissue is impaired [17,29]. …”

“…This is consistent with our previous finding that the homing and clearance of Eng -deficient macrophages in injury tissue (angiogenic region) are impaired [29]. The accumulation of macrophages in the angiogenic region of Eng -deficient mice could be due to persistent infiltration and delayed clearance of BM-derived macrophages.…”

“…We have also shown that Alk1 +/− BM-derived macrophages accumulate in Alk1 -deleted bAVM, and that CD34 + HHT monocytes are more likely to differentiate into macrophages in the angiogenic niche. Together with previous findings [17,24,29], these data suggest that deletion of one allele of Eng or perhaps Alk1 is sufficient to alter macrophage function, and that the abnormal macrophage function contributes to the accumulation of macrophages in bAVM.…”

The role of endoglin in post-ischemic revascularization

“…Furthermore, in an experimental model of brain arteriovenous malformations in mice induced by local injection of the VEGF gene, it has been reported that, compared with control mice, Eng-deleted mice show fewer macrophages homed to the angiogenic area 2 weeks after angiogenic stimulation [240]. This phenomenon can be explained by the reduced homing of monocytes in the injured tissue in Eng-deficient mice, as previously reported in other models [20,27,239]. However, Eng +/− animals showed more tissue macrophages at 8 weeks the stimulus, when arteriovenous malformations were already formed, resulting in persistent inflammation, which can be explained by an impaired clearance of Eng-deficient macrophages in the injured tissue (angiogenic region) [239,240].…”

“…In Eng +/− mice subjected to an experimental infarct, microvascularity within the infarct zone was strikingly lower than that in wild type mice, which resulted in a greater deterioration in cardiac function [20]. Moreover, after distal middle cerebral artery occlusion, Eng +/− mice showed larger infarct/atrophic volumes and fewer infiltrating macrophages than wild type animals, suggesting that endoglin deficiency impairs brain injury recovery by impairing macrophage homing, delaying inflammation resolution, and reducing angiogenesis [239]. Furthermore, in an experimental model of brain arteriovenous malformations in mice induced by local injection of the VEGF gene, it has been reported that, compared with control mice, Eng-deleted mice show fewer macrophages homed to the angiogenic area 2 weeks after angiogenic stimulation [240].…”