Flow-induced HDAC1 phosphorylation and nuclear export in angiogenic sprouting.
Angiogenesis requires the coordinated growth and migration of endothelial cells (ECs), with each EC residing in the vessel wall integrating local signals to determine whether to remain quiescent or undergo morphogenesis. These signals include vascular endothelial growth factor (VEGF) and flow-induced mechanical stimuli such as interstitial flow, which are both elevated in the tumor microenvironment. However, it is not clear how VEGF signaling and mechanobiological activation due to interstitial flow cooperate during angiogenesis. Here, we show that endothelial morphogenesis is histone deacetylase-1- (HDAC1) dependent and that interstitial flow increases the phosphorylation of HDAC1, its activity, and its export from the nucleus. Furthermore, we show that HDAC1 inhibition decreases endothelial morphogenesis and matrix metalloproteinase-14 (MMP14) expression. Our results suggest that HDAC1 modulates angiogenesis in response to flow, providing a new target for modulating vascularization in the clinic.
Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, 100 Blossom Street, Boston, Massachusetts 02114, USA.
Despina
D
Bazou
Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, 100 Blossom Street, Boston, Massachusetts 02114, USA.
Mei Rosa
MR
Ng
Department of Mechanical and Aerospace Engineering, Ohio State University, E406 201 W. 19th Avenue, Columbus, OH 43210, USA.
Jonathan W
JW
Song
Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, 100 Blossom Street, Boston, Massachusetts 02114, USA.
Shan Min
SM
Chin
Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, 100 Blossom Street, Boston, Massachusetts 02114, USA.
Nir
N
Maimon
Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, 100 Blossom Street, Boston, Massachusetts 02114, USA.
Lance L
LL
Munn
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