Key result
Endoglin deficiency worsens post-MI cardiac dysfunction, rescued by healthy but not HHT1 mononuclear cells.
Why the study?
HHT1 is caused by endoglin haploinsufficiency with heterogeneous clinical manifestations and severity, and the role of endoglin in vascular repair after myocardial infarction is unclear.
Does injection of healthy mononuclear cells rescue defective vascular repair and heart function in endoglin-deficient mice after myocardial infarction?
Does injection of healthy mononuclear cells rescue defective vascular repair and heart function in endoglin-deficient mice after myocardial infarction?
Endoglin deficiency impairs vascular repair after myocardial infarction, which can be rescued by healthy mononuclear cells, suggesting defective vascular repair contributes to HHT1 pathogenesis.
Defective mononuclear cell repair may underlie HHT1 heterogeneity; leaves open whether cell-based therapies could alter disease course.
BACKGROUND: Endoglin, an accessory receptor for transforming growth factor-beta in vascular endothelial cells, is essential for angiogenesis during mouse development. Mutations in the human gene cause hereditary hemorrhagic telangiectasia type 1 (HHT1), a disease characterized by vascular malformations that increase with age. Although haploinsufficiency is the underlying cause of the disease, HHT1 individuals show great heterogeneity in age of onset, clinical manifestations, and severity. METHODS AND RESULTS: In situ hybridization and immunohistochemical analysis of mouse and human hearts revealed that endoglin is upregulated in neoangiogenic vessels formed after myocardial infarction. Microvascularity within the infarct zone was strikingly lower in mice with reduced levels of endoglin (Eng+/-) compared with wild-type mice, which resulted in a greater deterioration in cardiac function as measured by magnetic resonance imaging. This did not appear to be because of defects in host inflammatory cell numbers in the infarct zone, which accumulated to a similar extent in wild-type and heterozygous mice. However, defects in vessel formation and heart function in Eng+/- mice were rescued by injection of mononuclear cells from healthy human donors but not by mononuclear cells from HHT1 patients. CONCLUSIONS: These results establish defective vascular repair as a significant component of the origin of HHT1. Because vascular damage or inflammation occurs randomly, it may also explain disease heterogeneity. More generally, the efficiency of vascular repair may vary between individuals because of intrinsic differences in their mononuclear cells.
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Laake et al. (2006) studied Myocardial infarction and Hereditary hemorrhagic telangiectasia type 1 (HHT1). Injection of mononuclear cells from healthy human donors vs. Mononuclear cells from HHT1 patients was evaluated on Microvascularity within the infarct zone and cardiac function. Mice with reduced endoglin levels exhibited lower microvascularity and greater deterioration in cardiac function after myocardial infarction, which was rescued by healthy human mononuclear cells but not by cells from HHT1 patients.