👤 Natalie Hoppe

This study aimed to examine the effects of weightlessness and microgravity, induced by parabolic flight, on specific biomarkers associated with angiogenesis, lipid homeostasis, and cardiovascular diseases, including angiogenin (ANG), angiopoietin-1 (ANGPT-1), angiopoietin-like protein 4 (ANGPTL4), heat shock protein 70 (HSP70), transforming growth factor-beta (TGF-β), vascular endothelial growth factor (VEGF), and platelet-derived growth factor subunit AA (PDGF-AA). 14 healthy volunteers (mean age: 28.9 years; 6 females) participated in short-term sessions of weightlessness and microgravity using parabolic flights. Venous blood samples were collected at different time points (baseline, 1 h, and 24 h after parabolic flight) and frozen as serum samples. Initially, Proteome Profiler Angiogenesis Array was used to screen pooled serum samples of each time point for potential alterations of angiogenesis-associated proteins. Additionally, individual blood samples were analyzed using enzyme-linked immunosorbent assay (ELISA). Proteome Arrays revealed an overall decrease of angiogenesis-associated proteins in response to parabolic flight. On the other hand, proteins associated with lipid homeostasis, such as Leptin and TIMP-4, were significantly elevated in response to parabolic flight. Individual analysis of selected proteins solely revealed a slight increase of ANGPTL4 and HSP70 levels 1 hour post-flight, although without statistical significance (p = 0.7705). Nevertheless, 24 h after parabolic flight, ANGPTL4 concentrations in serum significantly decreased compared to the preceding time point (p = 0.0020). Similarly, HSP70 was tendentially elevated 1 h after flight (p = 0.8135), though significantly declined at the end of the experiment (BL vs. 24 h: p = 0.0435; 1 h vs. 24 h: p = 0.0031). No significant differences could be observed in ANG, ANGPT1, TGF-β1, VEGF, and PDGF-AA concentrations at any time point. The findings of this study suggest that exposure to gravitational changes, such as weightlessness and microgravity, may lead to relevant changes in angiogenesis and lipid homeostasis. The upregulation of Leptin and TIMP-4, as well as ANGPTL4 in short-term response to parabolic flight poses a risk to disturbances in lipid metabolism, potentially increasing the likelihood of cardiovascular or hepatic events. Further research is needed to better understand the impact of microgravity and weightlessness on angiogenesis and lipid metabolism to protect astronaut health during prolonged space missions. Show less

The repertoire of adhesion receptors and ligands is supported by molecules, which are primarily recognized for their roles in immunity. We have recently shown that the co-stimulatory molecule CD40 ligand (CD154/CD40L) is pro-atherogenic and serves as an adhesive ligand for cells expressing the integrin Mac-1 (CD11b/CD18). Here, we studied the role of endothelial CD40L in several models of cardiovascular inflammation. We generated mice with an endothelial cell-specific deficiency of CD40L, Bmx-Cre In this functional validation study, we demonstrate that endothelial cell-expressed CD40L serves as an adhesion molecule in different models of acute inflammation in the aortic, peritoneal, mesenteric, and coronary vasculature. CD40L may therefore represent a promising therapeutic target at the interface of adaptive immunity and myeloid inflammation. Show less

Statins induce plaque regression characterized by reduced macrophage content in humans, but the underlying mechanisms remain speculative. Studying the translational APOE*3-Leiden.CETP mouse model with a humanized lipoprotein metabolism, we find that systemic cholesterol lowering by oral atorvastatin or dietary restriction inhibits monocyte infiltration, and reverses macrophage accumulation in atherosclerotic plaques. Contrary to current believes, none of (1) reduced monocyte influx (studied by cell fate mapping in thorax-shielded irradiation bone marrow chimeras), (2) enhanced macrophage egress (studied by fluorescent bead labeling and transfer), or (3) atorvastatin accumulation in murine or human plaque (assessed by mass spectrometry) could adequately account for the observed loss in macrophage content in plaques that undergo phenotypic regression. Instead, suppression of local proliferation of macrophages dominates phenotypic plaque regression in response to cholesterol lowering: the lower the levels of serum LDL-cholesterol and lipid contents in murine aortic and human carotid artery plaques, the lower the rates of in situ macrophage proliferation. Our study identifies macrophage proliferation as the predominant turnover determinant and an attractive target for inducing plaque regression. Show less

Glioblastoma multiforms (GBMs) are highly vascularized brain tumors containing a subpopulation of multipotent cancer stem cells. These cells closely interact with endothelial cells in neurovascular niches. In this study, we have uncovered a close link between the Notch1 pathway and the tumoral vascularization process of GBM stem cells. We observed that although the Notch1 receptor was activated, the typical target proteins (HES5, HEY1, and HEY2) were not or barely expressed in two explored GBM stem cell cultures. Notch1 signaling activation by expression of the intracellular form (NICD) in these cells was found to reduce their growth rate and migration, which was accompanied by the sharp reduction in neural stem cell transcription factor expression (ASCL1, OLIG2, and SOX2), while HEY1/2, KLF9, and SNAI2 transcription factors were upregulated. Expression of OLIG2 and growth were restored after termination of Notch1 stimulation. Remarkably, NICD expression induced the expression of pericyte cell markers (NG2, PDGFRβ, and α-smooth muscle actin [αSMA]) in GBM stem cells. This was paralleled with the induction of several angiogenesis-related factors most notably cytokines (heparin binding epidermal growth factor [HB-EGF], IL8, and PLGF), matrix metalloproteinases (MMP9), and adhesion proteins (vascular cell adhesion molecule 1 [VCAM1], intercellular adhesion molecule 1 [ICAM1], and integrin alpha 9 [ITGA9]). In xenotransplantation experiments, contrasting with the infiltrative and poorly vascularized tumors obtained with control GBM stem cells, Notch1 stimulation resulted in poorly disseminating but highly vascularized grafts containing large vessels with lumen. Notch1-stimulated GBM cells expressed pericyte cell markers and closely associated with endothelial cells. These results reveal an important role for the Notch1 pathway in regulating GBM stem cell plasticity and angiogenic properties. Show less