|Crosstalk between glioma-initiating cells and endothelial cells drives tumor progression.|
Jeon, HM; Kim, SH; Jin, X; Park, JB; Kim, SH; Joshi, K; Nakano, I; Kim, H
Glioma-initiating cells (GIC), which reside within the perivascular microenvironment to maintain self-renewal capacity, are responsible for glioblastoma initiation, progression, and recurrence. However, the molecular mechanisms controlling crosstalk between GICs and endothelial cells are poorly understood. Here, we report that, in both GICs and endothelial cells, platelet-derived growth factor (PDGF)-driven activation of nitric oxide (NO) synthase increases NO-dependent inhibitor of differentiation 4 (ID4) expression, which in turn promotes JAGGED1-NOTCH activity through suppression of miR129 that specifically represses JAGGED1 suppression. This signaling axis promotes tumor progression along with increased GIC self-renewal and growth of tumor vasculature in the xenograft tumors, which is dramatically suppressed by NOTCH inhibitor. ID4 levels correlate positively with NOS2 (NO synthase-2), HES1, and HEY1 and negatively with miR129 in primary GICs. Thus, targeting the PDGF-NOS-ID4-miR129 axis and NOTCH activity in the perivascular microenvironment might serve as an efficacious therapeutic modality for glioblastoma.
|SMAD3 deficiency promotes inflammatory aortic aneurysms in angiotensin II-infused mice via activation of iNOS.|
Tan, CK; Tan, EH; Luo, B; Huang, CL; Loo, JS; Choong, C; Tan, NS
Journal of the American Heart Association
Ninety percent of the patients carrying distinct SMAD3 mutations develop aortic aneurysms and dissections, called aneurysms-osteoarthritis syndrome (AOS). However, the etiology and molecular events downstream of SMAD3 leading to the pathogenesis of aortic aneurysms in these patients still remain elusive. Therefore, we aimed to investigate the vascular phenotypes of SMAD3-knockout mice.We have shown that angiotensin II-induced vascular inflammation, but not hypertension, leads to aortic aneurysms and dissections, ultimately causing aortic rupture and death in mice. Lipopolysaccharide-triggered inflammation confirmed that enhanced aortic macrophage recruitment was essential for aneurysm formation in angiotensin II-infused SMAD3-knockout mice. In contrast, phenylephrine-triggered hypertension alone was insufficient to induce aortic aneurysms in mice. Using uniaxial tensile and contractility tests, we showed that SMAD3 deficiency resulted in defective aortic biomechanics and physiological functions, which caused weakening of the aortic wall and predisposed the mice to aortic aneurysms. Chromatin immunoprecipitation (ChIP) and re-ChIP assays revealed that the underlying mechanism involved aberrant upregulation of inducible nitric oxide synthase (iNOS)-derived nitric oxide production and activation of elastolytic matrix metalloproteinases 2 and 9. Administration of clodronate-liposomes and iNOS inhibitor completely abrogated these aortic conditions, thereby identifying iNOS-mediated nitric oxide secretion from macrophages as the downstream event of SMAD3 that drives this severe pathology.Macrophage depletion and iNOS antagonism represent 2 promising approaches for preventing aortic aneurysms related to SMAD3 mutations and merit further investigation as adjunctive strategies for the life-threatening manifestations of AOS.