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Zhu et al. Endoglin and cerebral vascular diseases

INTRODUCTION the survival rate of stroke patients [19] . In addition,
increased angiogenesis was associated improvement
In human, endoglin gene (ENG, or CD105) is located of functional outcome in both animal models and
on chromosome 9q34.11. It is a type III transforming stroke patients [20-23] .
growth factor β (TGFβ) receptor interacting with
TGFβRI (TGFβ receptor, type I) and/or TGFβRII Mutations in the ENG gene are associated with type 1
[1]
(TGFβ receptor, type II) . In the endothelium, ENG hereditary hemorrhagic telangiectasia (HHT) [24] , also
interacts with the activin receptor-like kinase 1 (ALK1 known as Osler-Rendu-Weber Syndrome. HHT is an
or ACVRL1), a type 1 TGFβR. ENG binds with TGFβ1 autosomal dominant disease. The clinical features of
and TGFβ3 with high affinity in the presence of other HHT patients are telangiectases in mucocutaneous
TGFRs but not with TGFβ2 [1-4] . ENG also binds to membrane and arteriovenous malformation (AVM)
activin-A, bone morphogenetic protein 2 (BMP2) and in multiple organs, including the skin, liver, lung,
[1]
BMP7 . Protein studies suggested that ENG plays intestine and brain. AVMs are abnormal vessels that
an important role in modulating the TGFβ signaling shunt blood directly from arteries to veins [25] . Brain
[4]
pathway . AVM (bAVM) tends to rupture, which can cause life-
threatening intracranial hemorrhage and hemorrhagic
ENG gene expresses in many cell types, including stroke [25] . Hemorrhage from bAVM can also cause
endothelial cells [5,6] , activated monocytes and long-term disability. Elevated levels of angiogenic
[8]
[7]
macrophages , mesenchymal cells, fibroblasts , and factors including vascular endothelial growth factor
vascular smooth muscle cells [Table 1] [9,10] . Animals (VEGF) were found in sporadic bAVM patients [26,27] .
studies have revealed that ENG may be dispensable High levels of VEGF are also associated with increase
during vasculogenesis, a process from which primary of blood-brain barrier (BBB) permeability and bAVM
capillary plexus is formed; but ENG is required in hemorrhage [27-29] . Similarly, HHT patients that have a
angiogenesis, a process that remodels the primary higher incidence of AVMs in multiple organs also have
endothelial network into a mature circulatory system [11,12] . an increased level of plasma VEGF [30] . All of these
Immunohistochemical analysis showed that in normal evidence suggest that angiogenesis is involved in the
human brain, ENG is expressed in the endothelial pathogenesis of bAVM.
cells of brain vessels, as well as the endothelial
and adventitial layers of leptomeningeal arteries Since ENG plays an impor tant role in the
[Table 1] [13] . ENG expression is upregulated in angiogenesis, in this review, we summarize the
endothelial cells during wound healing and tumor influences of ENG on endothelial function and
vascularization, and in inflammatory tissues and the angiogenesis, as well as how ENG-deficiency
developing embryos [1,14,15] , indicating that ENG is an contributes to the pathogenesis of cerebrovascular
endothelial proliferation marker [16,17] . diseases, including ischemic stroke and intra-cranial
hemorrhage, as well as cerebrovascular malformation,
Ischemic stroke is caused by occlusion of a cerebral stenosis and occlusion.
artery. After ischemic stroke, blood supply to the
affected brain tissue is reduced, which leads to THE FUNCTION OF ENG GENE IN
oxygen deprivation to brain cells. Ischemia induces a ANGIOGENESIS
significant increase in microvascular density, a sign
of angiogenesis, in the penumbra of the cerebral To study the functional role of ENG in development,
[11,31]
infarct [18] . The degree of increased vessel-density in Eng gene knockout mice were generated .
the ischemic penumbra is positively correlated with Homozygous deletion of Eng gene in mice causes
embryonic death by E10.5-11.5 [11,31] . The endothelial
Table 1: Summary of ENG expression patterns in tissue cells derived from ENG deficient human embryonic
and cell lines stem cells failed to organize effectively into tubular
[12]
Tissue Tissue samples Cell lines structures in vitro . VEGF induced vascular network
Brain Humanendothelium [13] was also reducedin the metatarsal bone of Eng
-/-
Human adventitia [13] heterozygous knockout (Eng ) mouse embryo [12] .
Non-brain Human placenta [6] HUVEC [5] Consistently, depletion or inhibition of ENG gene in
Human spleen [7] HOON [6]
Murine ovary and uterus [8] U-937 [6,7] human endothelial cells mitigated VEGF-induced
Murine heart [8] HL-60 [7] angiogenesis [12] . These findings suggest that ENG
Murine muscle [8] Cultured monocytes [7] is required for the differentiation and sprouting of
Murine placenta [8] NCTC-2071 [8]
Murine spleen [8] VSMC [9] endothelial tubes, which are important processes of
HASMC [10] angiogenesis.
200 Neuroimmunology and Neuroinflammation ¦ Volume 4 ¦ October 17, 2017