Background and Objective:
Endoglin (Eng) deficiency causes hereditary hemorrhagic telangiectasia (HHT) and impairs myocardial repair. Pulmonary arteriovenous malformations in HHT patients are associated with a high incidence of paradoxical embolism in the cerebral circulation and ischemic brain injury. We hypothesized that Eng deficiency exacerbates ischemic brain injury.
Methods:
Eng heterozygous (
Eng
+/-
) mice and wild type (WT) mice underwent permanent distal middle cerebral artery occlusion (pMCAO). Infarct volume and CD68
+
cells were quantified 3 days and vascular density was determined 60 days after pMCAO. Behavior was assessed by corner test and adhesive removal test at 3, 15, 30 and 60 days after pMCAO. Matrix metalloproteinase 9
(Mmp9)
and
Notch1
expression in bone marrow (BM)-derived macrophages from
Eng
+/-
and WT were analyzed using real-time RT-PCR.
Results:
Eng
+/-
mice had a larger Infarct volume than WT mice (22±6% of the affected hemisphere vs. 16±6%, p=0.04).
Eng
+/-
mice had longer adhesive-removal time (p<0.05) and more frequent turning to the lesion side than WT mice at 15, 30 and 60 days (p<0.05) after pMCAO. Both groups had similar numbers of CD68
+
cells in the peri-infarct area at 3 days after pMCAO (370±80 vs 338±44 cells/mm
2
, p=0.37), but
Eng
+/-
mice had lower peri-infarct vessel density (417±69 vs 490±52 vessels/mm
2
, p=0.05) at 60 days after pMCAO. Up-regulation of
Mmp9
and
Notch1
expression in response to VEGF was attenuated in
Eng
+/-
BM-derived macrophages.
Conclusions:
Endoglin deficiency exacerbated brain injury and behavior dysfunction in mice after pMCAO and was associated with reduced angiogenesis. Although macrophage homing was not affected, reduced expression of two angiogenic-related genes,
Mmp9
and
Notch1
, by
Eng
+/-
BM-derived macrophages suggests a potential role of these cells in recovery from an ischemic injury.
Attenuation of Reactive Gliosis Does Not Affect Infarct Volume in Neonatal Hypoxic-Ischemic Brain Injury in Mice
