Page 204 - Read Online

Zhu et al. Endoglin and cerebral vascular diseases

stroke survivors [76] . suggesting that ENG deficiency impairs monocyte
adhesion and migration. In the acute phase (3 days)
ENG is expressed in proliferating vascular endothelial of stroke, Eng deficient mice had fewer macrophages
cells [77] and is elevated in inflammatory tissue and in the peri-infarct region [50] . However, at 60 days after
healing wound [78] . In patients, somepro-angiogenic stroke, a time that is considered as recovery stage,
genes, including Tie-2, matrix metalloproteinase-2 there was an increase number of macrophage in
(MMP-2), tissue inhibitor of matrix metalloproteinase-1 the peri-infarct region of Eng deficient animals [50] ,
(TIMP-1), hepatocyte growth factor-α (HGF-α) and suggesting a delayed homing and clearance of over-
monocyte chemoattractant protein-1 (MCP-1), were activated macrophage. However, the roles of post-
upregulated in ENG expressing micro-vessels ischemic inflammation might be bidirectional [84] . The
in stroke affected tissue. These key angiogenic inflammatory response after ischemic stroke could
elements play important roles in endothelial cell contribute to a secondary brain injury, because the
migration, differentiation and tube-formation, as well influx of inflammatory cells amplifies brain cell death.
as vessel stabilization and stem cell homing into the On the other hand, inflammation also facilitated the
region of angiogenesis and revascularization [79] . clearance of damaged tissues and promoted tissue
repair [85] . Therefore, the consequences of impaired
+/-
In Eng deficient mice (Eng mice), the functional macrophage in homing and clearance in the stroke
performance after stroke was poorer than wild type tissue require further studied.
animal both in the acute phase and the sub-chronic
stage (one month after stroke), suggesting that Interestingly, Eng mice had severer brain injury
+/–
there is an association between delayed functional than wild type mice since the first day of experimental
recovery and Eng deficiency [50] . The infarct volume stroke [50] , which could not be explained by impaired
+/-
and atrophic volume are larger in Eng mice [50] . tissue repair. As discussed in above, hypoxia induce
The density of micro-vessels within the infarct and endothelial Eng expression, which prevents hypoxia-
+/-
peri-infarct region are lower in Eng mice than wild induced apoptosis of endothelial cells. Therefore,
+/–
type mice [50,80] . In vitro study showed that Eng vascular damage in Eng +/– mice could be more
endothelial cells express a lower level of VEGF [81] severe than in wild type mice after ischemic injury. In
compared to that of wild type endothelial cells. addition, Eng haploinsufficiency has been shown to
Eng macrophages express lower levels of VEGF be associated with reduced production of nitric oxide
+/–
receptor 1 (VEGFR1) and 2 (VEGFR2) at the baseline and increased production of superoxide under eNOS
and lower level of VEGFR2 after VEGF stimulation induction [86] . Nitric oxide produced by endothelial
+/–
than wild type macrophages [42] . Although Eng cell induces vascular relaxation [87] . Bioavailability
+/–
macrophages and wild type macrophages express of nitric oxide is lower in Eng mice than in wild
similar levels of MMP9 at the baseline, unlike in type mice [88] . Enhancing superoxide production in
wild type macrophages, the expression of MMP9 Eng deficient mice reduces vascular relaxation, and
+/–
did not increase in Eng macrophages after VEGF increases vessel damage and oxidative stress, all of
treatment [42] . In the brain of Eng +/– mice, VEGF- which increases brain injury during the acute stage of
induced upregulation of VEGFR2 expression was also ischemic stroke.
impaired [82] . Together, these data suggest a reduced
angiogenic response in the absence of normal Eng Since ENG plays an important role in angiogenesis
function may be responsible for the impairment of and lack of ENG dampens angiogenesis, therapeutic
tissue repair in Eng deficient mice after experimental stimulation of ENG could promote angiogenesis,
stroke. vascular remodeling and improve stroke recovery,
as well as reduce morbidity and mortality of stroke
In addition, our study suggested that Eng deficiency patients.
is associated with impairment of macrophage
recruitment and clearance in the peri-infarct area CIRCULATING SOLUBLE ENG MODULATES
during stroke recovery [50] . Eng expression was CEREBRAL VASCULAR REMODELING
upregulated during the transition from monocyte to AND PLAYS ROLES IN VASOSPASM AFTER
macrophage . Eng deficiency in endothelial cell SUBARACHNOID HEMORRHAGE
[7]
reduced adhesion and transmigration of leukocytes
in response to ischemic injury [83] . Recruitment of Soluble ENG (sENG) is an alternative transcript of
monocytes to the infarcted tissue and subsequent ENG gene, which contains only the extracellular
vessel formation was severely impaired in HHT1 domain of the full-length ENG. Soluble ENG enters
patients (who have ENG haploinsufficiency) [80] the circulation in various conditions that related to
204 Neuroimmunology and Neuroinflammation ¦ Volume 4 ¦ October 17, 2017