Heparin impairs angiogenic signaling and compensatory lung growth after left pneumonectomy

Abstract

Children with hypoplastic lung diseases, such as congenital diaphragmatic hernia, can require life support via extracorporeal membrane oxygenation and systemic anticoagulation, usually in the form of heparin. The role of heparin in angiogenesis and organ growth is inconclusive, with conflicting data reported in the literature. This study aimed to investigate the effects of heparin on lung growth in a model of compensatory lung growth (CLG). Compared to the absence of heparin, treatment with heparin decreased the vascular endothelial growth factor (VEGF)-mediated activation of VEGFR2 and mitogenic effect on human lung microvascular endothelial cells in vitro. Compared to non-heparinized controls, heparinized mice demonstrated impaired pulmonary mechanics, decreased respiratory volumes and flows, and reduced activity levels after left pneumonectomy. They also had lower lung volume, pulmonary septal surface area and alveolar density on morphometric analyses. Lungs of heparinized mice displayed decreased phosphorylation of VEGFR2 compared to the control group, with consequential downstream reduction in markers of cellular proliferation and survival. The use of bivalirudin, an alternative anticoagulant that does not interact with VEGF, preserved lung growth and pulmonary mechanics. These results demonstrated that heparin impairs CLG by reducing VEGFR2 activation. These findings raise concern for the clinical use of heparin in the setting of organ growth or regeneration.

Lipopolysaccharide-induced murine lung injury results in long-term pulmonary changes and downregulation of angiogenic pathways

“…5). The use of exercise tolerance testing as a functional measurement of lung capacity is well established [28][29][30] . These results suggest that isolated LPS exposure contributes to impaired long-term functional capacity.…”

Investigation of the mechanisms of VEGF-mediated compensatory lung growth: the role of the VEGF heparin-binding domain

“…Prior work from our group demonstrated that exogenous, systemic VEGF164 therapy accelerates CLG in a murine model 13 , 14 . However, heparin, a commonly used anticoagulant in the clinical setting, impairs VEGF-mediated pulmonary growth and development 15 . VEGF164/165 and VEGF188/189 are well-known to interact with exogenous heparins and endogenous heparans via their HBD.…”

“…However, VEGF164 contains a heparin-binding domain (HBD), which interacts with heparin. Prior studies have revealed that exogenous heparin impairs VEGF-mediated accelerated CLG 15 . As heparin is the most commonly used anticoagulant, especially in patients requiring ECMO, the potentially deleterious interaction between VEGF and heparin is of particular concern.…”

Acute Lung Injury Associated Milieus Regulate the Plasticity of Type I Alveolar Cells via KLF2

“…One of the focus is on comprehensive views of all the differentiated epithelial cells. Dao et al [12] observed that lung regeneration transcriptomically retrieved lung development at alveoli forming stages after pneumonectomy, which suggested the possible dedifferentiation of differentiated lung cells. Park et al [13] found the dynamic changes in cell shape and gene expression in ciliated bronchiolar epithelial cells after naphthalene injury, which indicated ciliated cells transdifferentiate into other epithelial cell types.…”