PMID- 36718783
OWN - NLM
STAT- MEDLINE
DCOM- 20230201
LR  - 20230214
IS  - 1477-9137 (Electronic)
IS  - 0021-9533 (Linking)
VI  - 136
IP  - 2
DP  - 2023 Jan 15
TI  - Matrix stiffness regulates Notch signaling activity in endothelial cells.
LID - jcs260442 [pii]
LID - 10.1242/jcs.260442 [doi]
AB  - Notch signaling is critical for many developmental and disease-related processes. 
      It is widely accepted that Notch has a mechanotransduction module that regulates 
      receptor cleavage. However, the role of biomechanical properties of the cellular 
      environment in Notch signaling in general is still poorly understood. During 
      angiogenesis, differentiation of endothelial cells into tip and stalk cells is 
      regulated by Notch signaling, and remodeling of the extracellular matrix occurs. 
      We investigated the influence of substrate stiffness on the Notch signaling 
      pathway in endothelial cells. Using stiffness-tuned polydimethylsiloxane (PDMS) 
      substrates, we show that activity of the Notch signaling pathway inversely 
      correlates with a physiologically relevant range of substrate stiffness (i.e. 
      increased Notch signaling activity on softer substrates). Trans-endocytosis of 
      the Notch extracellular domain, but not the overall endocytosis, is regulated by 
      substrate stiffness, and integrin cell-matrix connections are both stiffness 
      dependent and influenced by Notch signaling. We conclude that mechanotransduction 
      of Notch activation is modulated by substrate stiffness, highlighting the role of 
      substrate rigidity as an important cue for signaling. This might have 
      implications in pathological situations associated with stiffening of the 
      extracellular matrix, such as tumor growth.
CI  - (c) 2023. Published by The Company of Biologists Ltd.
FAU - Kretschmer, Maibritt
AU  - Kretschmer M
AD  - Department of Pharmacy, Pharmaceutical Biology, Ludwig-Maximilians-Universitat 
      Munchen, Butenandtstrasse 5-13, 81377 Munich, Germany.
FAU - Mamistvalov, Rose
AU  - Mamistvalov R
AD  - The George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv 69978, 
      Israel.
FAU - Sprinzak, David
AU  - Sprinzak D
AUID- ORCID: 0000-0001-6776-6957
AD  - The George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv 69978, 
      Israel.
FAU - Vollmar, Angelika M
AU  - Vollmar AM
AD  - Department of Pharmacy, Pharmaceutical Biology, Ludwig-Maximilians-Universitat 
      Munchen, Butenandtstrasse 5-13, 81377 Munich, Germany.
FAU - Zahler, Stefan
AU  - Zahler S
AUID- ORCID: 0000-0002-5140-7287
AD  - Department of Pharmacy, Pharmaceutical Biology, Ludwig-Maximilians-Universitat 
      Munchen, Butenandtstrasse 5-13, 81377 Munich, Germany.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20230131
PL  - England
TA  - J Cell Sci
JT  - Journal of cell science
JID - 0052457
RN  - 0 (Receptors, Notch)
RN  - 0 (Calcium-Binding Proteins)
SB  - IM
MH  - *Endothelial Cells/metabolism
MH  - *Mechanotransduction, Cellular
MH  - Signal Transduction/physiology
MH  - Cell Differentiation
MH  - Extracellular Matrix/metabolism
MH  - Receptors, Notch/genetics/metabolism
MH  - Calcium-Binding Proteins/metabolism
MH  - Neovascularization, Physiologic/physiology
OTO - NOTNLM
OT  - Dll4
OT  - Endothelial cells
OT  - Mechanosensing
OT  - Notch1
OT  - Substrate stiffness
COIS- Competing interests The authors declare no competing or financial interests.
EDAT- 2023/02/01 06:00
MHDA- 2023/02/02 06:00
CRDT- 2023/01/31 05:23
PHST- 2022/07/18 00:00 [received]
PHST- 2022/12/22 00:00 [accepted]
PHST- 2023/01/31 05:23 [entrez]
PHST- 2023/02/01 06:00 [pubmed]
PHST- 2023/02/02 06:00 [medline]
AID - 286810 [pii]
AID - 10.1242/jcs.260442 [doi]
PST - ppublish
SO  - J Cell Sci. 2023 Jan 15;136(2):jcs260442. doi: 10.1242/jcs.260442. Epub 2023 Jan 
      31.