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Zhu et al. Endoglin and cerebral vascular diseases

in the AAV-VEGF induced brain angiogenic region in cells only, AVM formed in the skin around the ear
mice subjected to global Eng deletion at the age of wound and back wound [54,55] . We found that bAVM
8 weeks old [47] . The bAVM phenotype in these mice develops in the brain angiogenic region in Pdgfb-
highly resembled the phenotype of human bAVM [47] . iCreER; Eng 2f/2f mice that have Eng gene deletion
Furthermore, Eng-null endothelial cells were found specifically in endothelial cells. Myh11CreER-
in the dysplastic vessels in the bAVM lesion [47] . Our mediated Eng deletion in smooth muscle cells in adult
studies are consistent with the studies on skin AVM mice did not cause AVM formation in the wound area
development, and support the notion that an injury of the skin [54] . Furthermore, LysMCre; Eng 2f/2f mice,
(angiogenic stimulation) is needed to induce bAVM. which have Eng deleted in macrophages, did not
develop AVM in any organ and in the brain angiogenic
Eng-deficient bAVM mouse models have been used regions [47] . These studies indicate that Eng deletion in
to analyze the function of macrophages during bAVM endothelial cells is essential for AVM formation in the
pathogenesis. Although Eng deficiency has been brain and other organs [47,54] .
shown to impair monocyte migration into injured
tissue [48-50] , an increased number of bone barrow- Eng-deficient bAVM mouse models were valuable
derived macrophages and activated residential microglia resources to test new therapies for the treatment
was found in the bAVM lesion in mouse and human. of bAVM. Current treatments for bAVM are mostly
Compared with normal macrophages, Eng-deficient invasive and associated with high morbidities and
macrophages show slower but more persistent infiltration mortalities [56] . Since high VEGF level is involved in the
[51]
into the brain angiogenic regions . Delayed clearance pathogenesis of bAVM, we have tested the feasibility
of macrophages and persistent inflammation could of use soluble FMS-like tyrosine kinase 1 (sFLT1)
[51]
exaggerate abnormal vascular phenotypes in bAVM . gene therapy to treat bAVM. Soluble FLT1 is an
alternative transcript of FLT1 (or VEGFR1) containing
In addition to conditional knockout of Eng gene in only the extracellular domains of the receptor.
adult mice, several cell-specific cre transgenic mouse Soluble FLT1 binds VEGF with high affinity in tissue,
lines have been used to induction of Eng deletion reduces VEGF signaling through its membrane-
in specific cell-types. For example, the promoter of bound receptors, and thus inhibits VEGF-induced
SM22α (smooth muscle actin) is used express cre angiogenesis [14] . Systemic delivery of AAV9-sFLT1
in smooth muscle specifically. Although SM22α is into a bAVM mouse model that has Eng gene deleted
predominantly expressed in smooth muscle cells in globally reduced abnormal vessels in the bAVM
normal mice, Cre expression driven by the SM22α region [57] . Intravenous delivery of AAV9-sFLT1 to
promoter in this transgenic mouse line was also found SM22α Cre; Eng 2f/2f[57] mice that have spontaneously
in other cell types, including endothelial cells [52,53] . developed bAVMs reduced mortality and bAVM
SM22α Cre; Eng 2f/2f mice have Eng gene deleted in penetrance [57] . This study demonstrated that mouse
the SM22α expressing cells during the embryonic models are important tools to test new therapies.
developmental stage. We found 90% of SM22α Cre;
Eng 2f/2f mice have spontaneously developed bAVM HYPOXIA INDUCES ENG EXPRESSION
by 5 weeks of age and 50% of them died by 6 weeks
of age [47] . BAVM lesions varied in size and location Hypoxia induces the expression of ENG in human and
in these mice [47] . In addition to bAVMs, some of mouse brain microvascular endothelial cells [16,22,58] ,
SM22α Cre; Eng 2f/2f mice also developed spinal and which ameliorates endothelial cells apoptosis regardless
[59]
intestinal AVMs [47] . Because AVM develops in this of the presence or absence of TGFβ . During hypoxia
mouse line spontaneously without exogenous VEGF stress, TGFβ induces apoptosis of endothelial
stimulation, this model is an ideal model for testing cells [60,61] , but reduces the death of neurons [62] and
new therapeutic strategies. vascular smooth muscle cells [61] . Therefore, ENG is
likely to antagonize the inhibitory effects of TGFβ1
As mentioned above, Eng gene not only expresses in on human vascular endothelial cells [17,63] and protect
endothelial cells [5,6] , but also expresses in activated endothelial cells against apoptosis via TGFβ signaling
[7]
monocytes/macrophages , mesenchymal cells, or other independent pathways [59] .
[8]
fibroblasts , and smooth muscle cells [9,10] . Using
transgenes that express cre specific cell-types, the Under hypoxia conditions, ENG expression increases
Eng gene was conditionally deleted in different cell in many cell-types, such as, human microvascular
types in adult mice to determine which cell type is endothelial cells-1 (HMEC-1) and monocytic U-937
most crucial for AVM development [54,55] . In SclCreER; cell. It is likely that hypoxia regulates ENG expression
Eng 2f/2f mice, which have Eng deleted in endothelial through crosstalk of several signaling pathways [58] .
202 Neuroimmunology and Neuroinflammation ¦ Volume 4 ¦ October 17, 2017