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Hyperglycemia-induced vasculopathy in the murine vitelline vasculature: correlation with PECAM-1/CD31 tyrosine
1Departments of Pathology and Pediatrics, Yale University, Alexion Pharmaceuticals, Inc., New Haven, Connecticut, USA.
Insights
Maternal diabetes and hyperglycemia cause embryonic vascular defects by disrupting PECAM-1 signaling during blood vessel formation. Glucose regulation may prevent these developmental abnormalities.
Area of Science:
- Developmental Biology
- Cardiovascular Biology
- Endocrinology
Background:
- Maternal diabetes mellitus is linked to congenital abnormalities, particularly cardiovascular defects in offspring.
- The embryonic vascular system is crucial for organogenesis and develops through complex cell interactions.
- Platelet-endothelial cell adhesion molecule-1 (PECAM-1) plays a role in vasculogenesis and angiogenesis.
Purpose of the Study:
- To investigate the impact of hyperglycemia on embryonic vasculogenesis in the context of maternal diabetes.
- To determine the role of PECAM-1 tyrosine phosphorylation in hyperglycemia-induced embryonic vascular defects.
Main Methods:
- Cultured murine conceptuses exposed to hyperglycemia.
- Streptozotocin-induced diabetes model in pregnant mice.
- In vitro and in vivo analysis of yolk sac and embryonic vasculopathy.
- Assessment of PECAM-1 tyrosine phosphorylation during blood vessel formation.
Main Results:
- Hyperglycemia during gastrulation induced yolk sac and embryonic vasculopathy in mouse models.
- Vasculopathy was correlated with impaired PECAM-1 tyrosine dephosphorylation.
- Defective blood vessel formation was observed in angioblast clusters.
Conclusions:
- Hyperglycemia associated with maternal diabetes disrupts embryonic vascular development.
- Failure of PECAM-1 dephosphorylation is a key mechanism in hyperglycemia-induced vasculopathy.
- Glucose regulation during critical embryonic periods may mitigate vascular defects.
Abstract:
Maternal diabetes mellitus is associated with an increased incidence of congenital abnormalities as well as embryonic and perinatal lethality. In particular, a wide range of cardiovascular abnormalities have been noted in children of diabetic mothers and in the offspring of diabetic animals. The vascular system is the first organ system to develop in the embryo and is critical for normal organogenesis. The organization of mesodermal cells into endothelial and hematopoietic cells and into a complex vascular system is, in part, mediated by a series of specific cell-cell, cell-extracellular matrix, and cell-factor interactions. PECAM-1 expression has been observed during the earliest stages of vasculogenesis, and changes in PECAM-1 tyrosine phosphorylation have been associated with endothelial cell migration, vasculogenesis, and angiogenesis both in vitro and in vivo. In this report we demonstrate that exposure to hyperglycemia during gastrulation causes yolk sac and embryonic vasculopathy in cultured murine conceptuses and in the conceptuses of streptozotocin-induced diabetic pregnant mice. In addition, we correlate the presence of yolk sac and embryonic vasculopathy with the failure of PECAM-1 tyrosine dephosphorylation during the formation of blood islands/vessels from clusters of extra-embryonic and embryonic angioblasts in the murine conceptus using both in vitro and in vivo models. The importance of these findings in the development of vasculopathy in the offspring of diabetic mothers and the potential effects and benefits of glucose regulation during the periods of vasculogenesis/angiogenesis in embryonic development are discussed.