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Zhu et al. Endoglin and cerebral vascular diseases

ischemic stroke. As mentioned in earlier sections, perfusion and ENG expression [103] , the low spatial
ENG is expressed mainly in endothelial cells, resolution method used to evaluate the cerebral
smooth muscle cells and macrophages, which are blood flow of the entire MCA territory might not be
the three major cells involved in the pathogenesis accurate enough to detect the real perfusion through
of atherosclerosis [10] . The expression of ENG is very the MCA branches that were used to measure the
low in normal human arteries and is restricted to ENG expression. The increased expression of ENG
the endothelial cells of adventitial microvessels [10] . and HIF-1 in MMD is consistent with the increased
In contrast, higher ENG expression is present in the expression of ENG under hypoxia condition.
[10]
advanced atherosclerotic plaque of human patients . Therefore, ENG may play roles in the pathogenesis of
The site of ENG expression are slightly difference cerebrovascular stenosis or occlusion.
between atherosclerotic plaques in carotid arteries
and aorta. In aortic atherosclerotic plaque, ENG is THE PROSPECTIVE OF MODULATING
predominantly expressed in smooth muscle cells. ENG EXPRESSION FOR THE TREATMENT
However, in carotid plaque, ENG is expressed in OF CEREBROVASCULAR DISEASES
endothelial cells of neo-vessels within the lipid core
and plaque shoulders [98] . ENG expression is higher in Since ENG has been implicated in the pathogenesis
carotid plaque containing higher levels of collagen and of various cerebrovascular diseases [Table 2],
lessintra-plaque thrombi, which are characteristics modulation of ENG expression might be a potential
of stable plaques [99] . These evidence indicate that treatment for these conditions. Although currently
ENG may promote the formation of intra-plaque neo- there is no treatment available for patients with
vessels and collagen and reduce the vessel leakage human cerebrovascular diseases through targeting
and hemorrhage. However, ENG expression in the ENG, several agents that affect ENG expression
neo-vessels of carotid atherosclerosis has also been specifically or non-specifically, are clinical available
found to be positively correlated with the advanced for treating patients or are used in clinical trials.
grade of plaques [100] . The distinct ENG expression TRC105 is a chimeric IgG1monoclonal antibody
patterns in different types of plaques suggest that specifically against ENG that inhibits angiogenesis,
ENG might play different roles in the course of induces antibody-dependent cellular cytotoxicity
atherogenesis progression. (ADCC) and apoptosis of proliferating endothelium.
The safety and activity of TRC105 have been tested
Atorvastatin is a drug to treat carotid atherosclerotic in a Phase I and a preliminary Phase II clinical trials in
plague. In a mouse model of atherosclerosis, cancer patients [104] . Resveratrol is a natural component
atorvastatin treatment decreased the level of Eng of a number of fruits, including grapes, blueberries
in the serum and increased Eng expression in the and raspberries. The skin of red grapes is used to
plaque [101] . Therefore, Eng may serve as a biomarker extract resveratrol. In vitro, resveratrol reduces sENG
for evaluating the therapeutic effect of drugs in secretion and pro-inflammatory factors of cultured
treating atherosclerosis. More studies are needed endothelial cells [105] . Therefore, it might be a promising
to elucidate the role of ENG in the pathogenesis of non-specific inhibitor of sENG. A proper level of ENG
atherosclerosis. expression might be crucial for maintaining normal
angiogenesis and vascular remodeling in the brain.
Moyamoya disease (MMD) is a rare, progressive However, there is no report of direct regulation of
cerebrovascular disorder caused by blocked arteries at ENG for treating cerebrovascular disease to date.
the base of the brain in an area called the basal ganglia. In vitro study showed that statins could increase
MMD is one of the major causes of stroke in children sENG secretion from endothelial cells [106] ; and in vivo
and adults characterized by progressive stenosis or administration of stain increased Eng expression in
occlusion of terminal portion of internal carotid arteries the carotid plaque of a mouse model [101] . Statins are
and development of fragile collateral vessels [102] . Middle a group of medications that has been used to treat
cerebral artery (MCA) of MMD patients had thicker patients with carotid artery atherosclerosis and other
intimal walls than control vessels collected from ischemic cerebrovascular diseases. More studies are
aneurysm patients [103] , indicating intimal hyperplasia needed to test whether ENG can be used as a target
in MMD. The expression of ENG and HIF-1 are for developing new therapies for the treatment of
increased in the intima of MMD patients [103] . In cerebrovascular diseases.
addition, TGFβ3 expression was also detected, which
was predominantly in the endothelium and was co- CONCLUSION
localized with HIF-1 and ENG [103] . Although the study
did not find an association between cerebral blood In summary, ENG plays a critical role in angiogenesis,
206 Neuroimmunology and Neuroinflammation ¦ Volume 4 ¦ October 17, 2017