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Zhu et al. Endoglin and cerebral vascular diseases

the endothelial injury, activation, inflammation and be a predictive factor for the long-term outcome, such
senescence [89] . Our group showed that sENG level is as, 6 months after SAH [95] . Similar to sENG, the ENG
increased in the surgical resected human bAVMs [90] . positive endothelial micro-particles were increased in
We have also shown that co-injection of an adenoviral SAH patients with vasospasm [96] .
vector expressing sENG with AAV-VEGF into mouse
brains caused capillary dysplasia. It is still unclear Soluble ENG are present in both healthy people
how overexpression of sENG causes cerebrovascular and patients with pathological conditions (such as
malformation. One of the possibilities is that circulating preeclampsia and SAH) [89] . Several studies suggest
sENG acts as a decoy inhibiting the effect of ENG that sENG is a naturally occurring antagonist of
on the endothelium, leading to vascular malformation TGFβ [97] . In contrast to the lower level of sENG, the
during angiogenesis. level of TGFβ1 in the serum was higher in patients
with vasospasm after SAH than those without
Nitric oxide (NO) is a potent vascular smooth muscle vasospasm [95] . Moreover, sENG interferes the binding
relaxant, which is synthesized by the vascular between TGFβ1 and its receptors [89] . TGFβ1 has
+/-
endothelium. Eng mice have a lower level of NO been suggested to be involved in eNOS activation [89] .
metabolites (nitrites) in the plasma and in the urine Therefore, the reduced sENG levels in patients with post-
than that of wild type mice [91] , suggesting that the SAH vasospasm might reflect an impaired production
NO level is lower in Eng deficient animals. The of vasorelaxant factors, such as NO. However, there
hypotensive and vasodilatory response induced is no direct evidence supporting the cause-and-effect
by endothelium-dependent vasodilators was less relationship between vasospasm and sENG. Further
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intensive in Eng mice than wild type mice. However, studies of post-SAH vasospasm in Eng-deficient mice
the difference of this vasodilation effect between might be helpful in exploring the association of sENG
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Eng mice and wild type mice disappeared after NO and vasorelaxation.
synthesis was inhibited [91] . These findings suggested
that the NO level or the subsequent vessel response Interestingly, the changes of sENG in the
+/-
to NO is reduced in Eng mice. However, after cerebrospinal fluid (CSF) and the serum of patients
eliminating the endogenous NO, the vasodilatory with SAH and vasospasm are opposite [94,95] . In
effect induced by exogenous NO donor (nitroprusside) patients with Doppler sonographic vasospasm, the
+/-
was similar in Eng and wild type mice [91] . The serum level of sENG was similar to those without
peripheral progenitor cells of HHT patients expresses vasospasm [95] . However, the serum level of sENG
lower level of eNOS (endothelial nitric oxide synthase) was reduced in patients with cerebral infarction due to
[92]
mRNA . Endothelial NOS produces NO in response severe vasospasm and hydrocephalus [95] , suggesting
to humoral and mechanical stimuli. However, that the sENG level in the serum might beserved
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resistance arteries in Eng mice displayed an eNOS- as a biomarker for cerebral ischemia subsequent
dependent impairment in the myogenic response to vasospasm. Cerebral hypo-perfusion or hypoxia
(normal resistance arteries contract in response to could induce increases of focal expression of ENG
increases of perfusion pressure) despite of a reduced and might contribute to the increase of sENG in the
eNOS level. Eng deficient endothelial cells had CSF of patients with vasospasm. Both extravasation
uncoupled eNOS, which produce less NO but more of sENG from blood or intrathecal production of sENG
superoxide [86] . Taken together, these studies indicate could cause the increase of sENG in the CSF and
a role of Eng in the regulation of vascular tone. decrease of sENG in the plasma. Further studies are
needed to ravel the origin of sENG during post-SAH
Cerebral vasospasm is one of the most common vasospasm.
complications of subarachnoid hemorrhage (SAH) and
is associated with high morbidity and mortality. NO is Although it is not clear how ENG-positive micro-
[93]
found to be an important mediator of vasospasm . The particles and sENG increased in patients with
potential role of ENG on the production of NO suggests post-SAH vasospasm, the results of these studies
that ENG might be associated with vasospasm after indicated that, the circulating sENG is a promising
SAH. In patients with SAH, the level of sENG increased biomarker for cerebral vasospasm after SAH.
in the cerebrospinal fluid (CSF) and decreased in the
serum [94,95] . In the subgroup with cerebral infarction due ALTERNATIONS OF ENG EXPRESSION
to post-SAH vasospasm, the level of sENG was higher IN ATHEROSCLEROTIC PLAQUES AND
in the CSF and lower in the serum than the patients STENOTIC CEREBRAL VESSELS
who did not have post-SAH cerebral infarction [94,95] . The
level of sENG during the first two weeks of SAH might Carotid atherosclerotic stenosis is a major cause of
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