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Zhu et al. Endoglin and cerebral vascular diseases

The transcriptional regulation of ENG expression under circulating cells as a self-repair response to stroke
hypoxia condition was studied by a reporter assay or a sign of increased apoptosis of circulating cells in
using HeLa cells, and by the electrophoretic mobility response to hypoxic conditions [69] .
shift assay (EMSA) using human umbilical cord vein
endothelial cells (HUVECs). These assays confirmed The role of ENG in stroke injury is complex, and is
the presence of a hypoxia response element (HRE) influenced by the local microenvironment. Constitutive
in the enhancer region of ENG gene [64] . Therefore, expression of ENG enhances the TGFβ signaling
ENG expression can be induced by hypoxia through and promotes new vessel wall remodeling [11] . ENG
hypoxia-inducible factor-1 (HIF-1). A subsequent study overexpression also protects against TGFβ-induced
suggested that hypoxic induction of Eng expression in apoptosis of endothelial cells [17,59] . Reduction of vascular
bEnd.3 (a mouse brain endothelial cell line) cells was cell-apoptosis after hypoxia improves blood supply to
[16]
activated through ERK-p38 MAPK and JNK pathway , ischemic tissue [58,71] . Increase of ENG expression in
[58]
instead of HIF-1 . In addition, Smad3 was reported to endothelial cells could also be hazardous, because
interact with HIF proteins to induce the overexpression BBB permeability was increased in some of the
of ENG [64] . Although these studies implicated links capillaries that express high level of ENG, which
among multiple factors, further studies are required to was accompanied with mononuclear cell infiltration
better elucidate the exact transcriptional regulation of in the surrounding brain tissues [72] . These findings
ENG expression under hypoxia conditions. suggests that pronounced ENG overexpression might
impair vessel wall integrity. Alternatively, lack of ENG
ENG EXPRESSION IS UPREGULATED AFTER expression may indicate severe vessel damage [72] .
STROKE INJURY ENG and TGFβ are involved in the pathogenesis of
post-ischemic brain injury in human. Abnormal ENG
Previous studies revealed that ENG was highly and TGFβfunction might lead to long-term neurological
expressed in the penumbra region of human stroke deterioration or cognitive disturbance after acute
lesion, where an increase of angiogenesis was ischemic stroke [72,73] . Homeostasis of ENG expression
found [22] . However, it was not clear at that time is crucial for maintaining normal angiogenesis, vascular
whether the angiogenesis was beneficial. In acute remodeling and reduction of stoke injury.
ischemic stroke patients, there is a robust mobilization
of immature hematopoietic cells, colony-forming cells THE EFFECT OF ENG DEFICIENCY IN
and long-term culture initiating cells [65] . It has been ISCHEMIC STROKE INJURY
suggested that the degree of immature hematopoietic
cell mobilization is directly correlated with the The survival of neurons in peri-infarcted regions
recovery of neurological function [66,67] . An increase of is associated with the extent of patient recovery
ENG positive micro-particles including exosomes and after stroke [74] . Nutrient supply supporting neuron
shedding vesicles, which are small vesicles released survival is carried through blood. Higher microvessel
by specific cells (endothelial or MSC) [68] , were density in the peri-infarct region is associated with
detected in patients’ sera collected 3 days after stroke lower morbidity and mortality [22] . Hypoxia-induced
compared to that of healthy people [69] . Certain types angiogenesis increases blood flow and oxygen
of ENG positive micro-particles increased further delivery to ischemic tissues, which contributes to the
in stroke patients with severe disability. The ENG recovery after stroke [28] .
positive micro-particles decreased gradually after the
initial increases [69] . The number of these circulating Angiogenesis occurs in human brain after stroke.
ENG positive micro-particles was positively correlated Through examining human postmortem brain samples
with the stroke severity, even after adjusting for with ischemic infarcts caused by occlusive vascular
other demographic and clinical variables, such diseases, capillary networks with regular connection
as hypotension and other stroke comorbidities [69] . and micro-vessels were found in the brain samples
Similarly, ENG positive circulating micro-particles of patients who died within one week after stroke,
released from endothelial cells were also increased in and the neo-vasculature was in filled with blood in
patients with acute ischemic stroke. The increase of the brain samples collected from patients that died
ENG positive cells was positively associated with the 2-3 weeks after stroke [75] . The micro-vessel density
severity of neurological function at hospital admission, remains higher in the infarct area compared with the
larger brain lesion volume and unfavorable functional corresponding contralateral side three months after
outcome at hospital discharge [70] . The increased level stroke [22] . Increased vessel density restores cerebral
of circulating ENG positive micro-particles after acute blood flow, salvages ischemic tissue, enhances
stroke may have been caused by either increased neuronal survival and improves functional recovery of
Neuroimmunology and Neuroinflammation ¦ Volume 4 ¦ October 17, 2017 203