Abstract
Myeloid angiogenic cells (MAC) derive from hematopoietic stem/progenitor cells (HSPCs) that are mobilized from the bone marrow. They home to sites of neovascularization and contribute to angiogenesis by production of paracrine factors. The number and function of proangiogenic cells are impaired in patients with diabetes or cardiovascular diseases. Both conditions can be accompanied by decreased levels of heme oxygenase-1 (HMOX1), cytoprotective, heme-degrading enzyme. Our study is aimed at investigating whether precursors of myeloid angiogenic cells (PACs) treated with known pharmaceuticals would produce media with better proangiogenic activity in vitro and if such media can be used to stimulate blood vessel growth in vivo. We used G-CSF-mobilized CD34+ HSPCs, FACS-sorted from healthy donor peripheral blood mononuclear cells (PBMCs). Sorted cells were predominantly CD133+. CD34+ cells after six days in culture were stimulated with atorvastatin (AT), acetylsalicylic acid (ASA), sulforaphane (SR), resveratrol (RV), or metformin (Met) for 48 h. Conditioned media from such cells were then used to stimulate human aortic endothelial cells (HAoECs) to enhance tube-like structure formation in a Matrigel assay. The only stimulant that enhanced PAC paracrine angiogenic activity was atorvastatin, which also had ability to stabilize endothelial tubes in vitro. On the other hand, the only one that induced heme oxygenase-1 expression was sulforaphane, a known activator of a HMOX1 inducer—NRF2. None of the stimulants changed significantly the levels of 30 cytokines and growth factors tested with the multiplex test. Then, we used atorvastatin-stimulated cells or conditioned media from them in the Matrigel plug in vivo angiogenic assay. Neither AT alone in control media nor conditioned media nor AT-stimulated cells affected numbers of endothelial cells in the plug or plug's vascularization. Concluding, high concentrations of atorvastatin stabilize tubes and enhance the paracrine angiogenic activity of human PAC cells in vitro. However, the effect was not observed in vivo. Therefore, the use of conditioned media from atorvastatin-treated PAC is not a promising therapeutic strategy to enhance angiogenesis.
Highlights
Development of new blood vessels is necessary for the effective tissue regeneration
We have recently shown that myeloid angiogenic cells (MAC) isolated from the bone marrow of Hmox1 knockout mice present impaired proliferation, migration, and formation of capillaries [27]
Paracrine angiogenic activity is considered as a critical role played by myeloid angiogenic cells in the regulation of blood vessel formation
Summary
Development of new blood vessels is necessary for the effective tissue regeneration. The mechanisms which allow for the regulation of angiogenesis are of great importance. The process of neovascularization can be influenced by the residual endothelial cells and by the circulating cells. Such myeloid angiogenic cells (MAC) [1] of bone marrow origin were known as endothelial progenitor cells (EPCs). EPCs are enriched in the population coexpressing CD34, CD133, and KDR with a low or absent expression of pan-hematopoietic marker CD45 [1]. They can bind Ulex europaeus lectin and acetylated lowdensity lipoprotein (LDL) [2]
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