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Flow-induced HDAC1 phosphorylation and nuclear export in angiogenic sprouting

View Article: PubMed Central - PubMed

ABSTRACT

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.

No MeSH data available.


Related in: MedlinePlus

Potential role of HDAC1 in flow-induced angiogenesis.Interstitial (Transwall) flow and VEGF result in increased HDAC1 phosphorylation in the nucleus as well as HDAC1 nuclear export. Nuclear export (dashed blue line) can be reduced with LMB treatment while HDAC1 activity, but not phosphorylation, can be reduced via DHOB treatment. HDAC1 increases MMP14 expression, potentially through its role as a transcriptional regulator. VEGFR2 phosphorylation is integral for both static and flow-induced angiogenic sprouting as revealed by the blocking experiments with sunitinib. HDAC1 appears to complement and amplify the VEGF pathway when flow signals are present.
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f6: Potential role of HDAC1 in flow-induced angiogenesis.Interstitial (Transwall) flow and VEGF result in increased HDAC1 phosphorylation in the nucleus as well as HDAC1 nuclear export. Nuclear export (dashed blue line) can be reduced with LMB treatment while HDAC1 activity, but not phosphorylation, can be reduced via DHOB treatment. HDAC1 increases MMP14 expression, potentially through its role as a transcriptional regulator. VEGFR2 phosphorylation is integral for both static and flow-induced angiogenic sprouting as revealed by the blocking experiments with sunitinib. HDAC1 appears to complement and amplify the VEGF pathway when flow signals are present.

Mentions: Extravasating or intravasating plasma creates forces that affect endothelial cells in the vessel wall, but it is not clear how the mechanobiological signals are propagated. Our results show that HDAC1 is a key component of this mechano-signaling pathway. In functional assays, inhibition of HDAC1 suppressed EC morphogenesis under flow but not under static conditions, and interstitial flow increased the phosphorylation of HDAC1 at Ser421 as well as its activity. The observed increase in activity after phosphorylation is consistent with other reports35. Although fluid forces activate morphogenesis, this mechanism is also dependent on VEGFR2 activation, as blocking this pathway completely inhibited morphogenesis in our system, regardless of the presence of flow. Furthermore, flow did not increase HDAC1 phosphorylation in the absence of VEGFR2 activation. These results suggest that HDAC1 acts downstream of VEGF in its regulation of angiogenic invasion by activating additional effectors or amplifying existing pathways (Fig. 6).


Flow-induced HDAC1 phosphorylation and nuclear export in angiogenic sprouting
Potential role of HDAC1 in flow-induced angiogenesis.Interstitial (Transwall) flow and VEGF result in increased HDAC1 phosphorylation in the nucleus as well as HDAC1 nuclear export. Nuclear export (dashed blue line) can be reduced with LMB treatment while HDAC1 activity, but not phosphorylation, can be reduced via DHOB treatment. HDAC1 increases MMP14 expression, potentially through its role as a transcriptional regulator. VEGFR2 phosphorylation is integral for both static and flow-induced angiogenic sprouting as revealed by the blocking experiments with sunitinib. HDAC1 appears to complement and amplify the VEGF pathway when flow signals are present.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC5037418&req=5

f6: Potential role of HDAC1 in flow-induced angiogenesis.Interstitial (Transwall) flow and VEGF result in increased HDAC1 phosphorylation in the nucleus as well as HDAC1 nuclear export. Nuclear export (dashed blue line) can be reduced with LMB treatment while HDAC1 activity, but not phosphorylation, can be reduced via DHOB treatment. HDAC1 increases MMP14 expression, potentially through its role as a transcriptional regulator. VEGFR2 phosphorylation is integral for both static and flow-induced angiogenic sprouting as revealed by the blocking experiments with sunitinib. HDAC1 appears to complement and amplify the VEGF pathway when flow signals are present.
Mentions: Extravasating or intravasating plasma creates forces that affect endothelial cells in the vessel wall, but it is not clear how the mechanobiological signals are propagated. Our results show that HDAC1 is a key component of this mechano-signaling pathway. In functional assays, inhibition of HDAC1 suppressed EC morphogenesis under flow but not under static conditions, and interstitial flow increased the phosphorylation of HDAC1 at Ser421 as well as its activity. The observed increase in activity after phosphorylation is consistent with other reports35. Although fluid forces activate morphogenesis, this mechanism is also dependent on VEGFR2 activation, as blocking this pathway completely inhibited morphogenesis in our system, regardless of the presence of flow. Furthermore, flow did not increase HDAC1 phosphorylation in the absence of VEGFR2 activation. These results suggest that HDAC1 acts downstream of VEGF in its regulation of angiogenic invasion by activating additional effectors or amplifying existing pathways (Fig. 6).

View Article: PubMed Central - PubMed

ABSTRACT

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.

No MeSH data available.


Related in: MedlinePlus