Letter by Jian et al Regarding Article, “Bone Marrow Endothelial Cells Regulate Myelopoiesis in Diabetes Mellitus”

We have read with great interest the article published in Circulation by Hoyer et al, 1 which showed that bone marrow endothelial cells participate in the dysregulation of bone marrow hematopoiesis, and enhanced endothelial epithelial growth factor receptor (Egfr) signaling dampens excessive myelopoiesis in diabetes.We believe that the following points should be considered.First, emerging evidence suggests that the pathogenesis of various cardiovascular disorders is associated with the cognate ligand-independent Egfr activation referred to as transactivation.Endothelial Egfr can be transactivated by factors related to diabetes and obesity, such as endothelin-1, angiotensin II, and leptin. 2 Amphiregulin might not be the main source that mediates Egfr activation despite the authors having found its high expression in the serum of diabetic mice.In addition, as for vascular smooth muscle cell, increased Egfr signaling is detrimental rather than protective, 2 which increases difficulties for endothelial cell-specific drug development in the future.Second, the authors showed that Ang1 (angiopoietin-1) endothelial expression was significantly decreased in diabetic Cdh5 Cre Egfr fl/fl mice in comparison with controls, but they did not measure Ang2 (angiopoietin-2) expression.Ang1 maintains endothelial quiescence and integrity through binding to Tie2 receptor, whereas Ang2 acts as a context-dependent Tie2 antagonist interfering with Ang1-induced Tie2 phosphorylation. 3Vascular permeability will be significantly augmented when Ang1/Ang2 balance is in favor of Ang2, which allows more direct interaction of blood molecules, S100A8/A9, for example, with hematopoietic stem and progenitor cells.Circulating S100A8/A9 produced by neutrophils is a well-established factor that promotes myelopoiesis through the receptor for advanced glycation end products on myeloid progenitor cells. 4Thus, this endothelial effect of Ang/Tie2 signaling disrupted by Egfr deletion on regulating myelopoiesis should not be neglected.Likewise, Ang/Tie2 signaling can also influence inflammation and play a role in atherosclerosis, 5 which may contribute to plaque formation independently of enhanced myelopoiesis in diabetic Cdh5 Cre Egfr fl/fl mice.We think that readers would have benefited if the authors had discussed these issues.