Abstract
Angiogenesis is a fundamental process during development and disease, and many details of the underlying molecular and cellular mechanisms are incompletely understood. Mitogen-activated protein kinase (MAPK)-activated protein kinase 2 (MK2), a major downstream target of p38 MAPK, has recently been identified as a regulator of Interleukin 1β dependent angiogenesis in vivo, and in vitro data suggest a role of MK2 for VEGF-dependent angiogenic processes in endothelial cells. We thus hypothesized that MK2 plays a role during physiological vascular development in vivo.Vascular development was investigated in the retina of MK2-deficient mice. Retinal angiogenesis such as sprouting, branching and pruning was unchanged in MK2-/- mice compared to wildtype littermates. Early arterial development was also comparable between genotypes. However, with further expansion of vascular smooth muscle cells (SMC) during maturation of the arterial network at later time points, the number of arterial branch points was significantly lower in MK2-/- mice, resulting in a reduced total arterial area in adult mice. Isolated aortic smooth muscle cells from MK2-/- mice showed a more dedifferentiated phenotype in vitro and downregulation of central SMC marker genes, consistent with the known impaired migration of MK2-/- SMC.In conclusion, MK2 is not required for physiological retinal angiogenesis. However, its loss is associated with an altered genetic profile of SMC and an impaired arterial network in adult mice, indicating a distinct and probably cell-specific role of MK2 in arteries.Electronic supplementary materialThe online version of this article (doi:10.1186/s13221-016-0038-2) contains supplementary material, which is available to authorized users.
Highlights
Vascular development in higher organisms consists of two principal mechanisms: Angiogenesis, i.e. endothelial sprouting, branching, and pruning, and subsequent remodelling of the endothelial network towards a complex 3dimensional system of arteries, capillaries and veins [ 1]
We show that retinal angiogenesis is unaffected in the absence of MAPK-activated protein kinase 2 (MK2) but arterial network phenotype is impaired, which might be attributed to a cell-specific role of MK2 in vascular smooth muscle cells (SMC)
This process was unchanged in MK2 KO mice as assessed by measuring the area covered by the endothelial cell (EC) network over time, indicating that there is no gross sprouting angiogenesis defect in MK2 KO mice
Summary
Vascular development in higher organisms consists of two principal mechanisms: Angiogenesis, i.e. endothelial sprouting, branching, and pruning, and subsequent remodelling of the endothelial network towards a complex 3dimensional system of arteries, capillaries and veins [ 1]. With expansion of the endothelial network vascular smooth muscle cells (SMC) cover preformed endothelial tubes, as a core step of development of the arterial system [ 5]. Key components of the molecular control of angiogenesis are vascular endothelial growth factor (VEGF) as well as Notch ligands and their cognate receptors [ 1]. P38 MAP-kinase (MAPK) and its downstream effector MAPK-activated protein kinase 2 (MK2) are central regulators of sprouting, migration, proliferation, and actin polymerization in several cell types [ 8]. MK2 has recently been identified as an essential downstream component of IL-1β induced angiogenesis in vitro and in vivo [ 9].
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