Fluid shear stress regulates placental growth factor expression via heme oxygenase 1 and iron

AbstractIncreased fluid shear stress (FSS) is a key initiating stimulus for arteriogenesis, the outward remodeling of collateral arterioles in response to upstream occlusion. Placental growth factor (PLGF) is an important arteriogenic mediator. We previously showed that elevated FSS increases PLGF in a reactive oxygen species (ROS)-dependent fashion both in vitro and ex vivo. Heme oxygenase 1 (HO-1) is a cytoprotective enzyme that is upregulated by stress and has arteriogenic effects. In the current study, we used isolated murine mesentery arterioles and co-cultures of human coronary artery endothelial cells (EC) and smooth muscle cells (SMC) to test the hypothesis that HO-1 mediates the effects of FSS on PLGF. HO-1 mRNA was increased by conditions of increased flow and shear stress in both co-cultures and vessels. Both inhibition of HO-1 with zinc protoporphyrin and HO-1 knockdown abolished the effect of FSS on PLGF. Conversely, induction of HO-1 activity increased PLGF. To determine which HO-1 product upregulates PLGF, co-cultures were treated with a CO donor (CORM-A1), biliverdin, ferric ammonium citrate (FAC), or iron-nitrilotriacetic acid (iron-NTA). Of these FAC and iron-NTA induced an increase PLGF expression. This study demonstrates that FSS acts through iron to induce pro-arteriogenic PLGF, suggesting iron supplementation as a novel potential treatment for revascularization.

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Fluid Shear Stress Regulates Placental Growth Factor Expression via Heme Oxygenase 1 and Iron

10.21203/rs.3.rs-493214/v1 ◽

2021 ◽

Author(s):

Nabil A. Rashdan ◽

Bo Zhai ◽

Pamela C. Lovern

Keyword(s):

Shear Stress ◽

Growth Factor ◽

Heme Oxygenase ◽

Fluid Shear Stress ◽

Placental Growth Factor ◽

Ammonium Citrate ◽

Ferric Ammonium Citrate ◽

Heme Oxygenase 1 ◽

Zinc Protoporphyrin ◽

Fluid Shear

Abstract Increased fluid shear stress (FSS) is a key initiating stimulus for arteriogenesis, the outward remodeling of collateral arterioles in response to upstream occlusion. Placental growth factor (PLGF) is an important arteriogenic mediator. We previously showed that elevated FSS increases PLGF in a reactive oxygen species (ROS)-dependent fashion both in vitro and ex vivo. Heme oxygenase 1 (HO-1) is a cytoprotective enzyme that is upregulated by stress and has arteriogenic effects. In the current study, we used isolated murine mesentery arterioles and cocultures of human coronary artery endothelial cells (EC) and smooth muscle cells (SMC) to test the hypothesis that HO-1 mediates the effects of FSS on PLGF. HO-1 mRNA was increased by conditions of increased flow and shear stress in both cocultures and vessels. Both inhibition of HO-1 with zinc protoporphyrin and HO-1 knockdown abolished the effect of FSS on PLGF. Conversely, induction of HO-1 activity increased PLGF. To determine which HO-1 product upregulates PLGF, cocultures were treated with a CO donor (CORM-A1), biliverdin, ferric ammonium citrate (FAC), or iron-nitrilotriacetic acid (iron-NTA). Of these FAC and iron-NTA induced an increase PLGF expression. This study demonstrates that FSS acts through iron to induce pro-arteriogenic PLGF, suggesting iron supplementation as a novel potential treatment for revascularization.

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PGC1α Regulates the Endothelial Response to Fluid Shear Stress via Telomerase Reverse Transcriptase Control of Heme Oxygenase-1

10.1101/2021.05.26.445830 ◽

2021 ◽

Author(s):

Shashi Kant ◽

Khanh-Van Tran ◽

Miroslava Kvandova ◽

Amada D. Caliz ◽

Hyung-Jin Yoo ◽

...

Keyword(s):

Shear Stress ◽

Reverse Transcriptase ◽

Heme Oxygenase ◽

Fluid Shear Stress ◽

Heme Oxygenase 1 ◽

Telomerase Reverse Transcriptase ◽

Fluid Shear ◽

Flow Alignment

Fluid shear stress (FSS) is known to mediate multiple phenotypic changes in the endothelium. Laminar FSS (undisturbed flow) is known to promote endothelial alignment to flow that is key to stabilizing the endothelium and rendering it resistant to atherosclerosis and thrombosis. The molecular pathways responsible for endothelial responses to FSS are only partially understood. Here we have identified peroxisome proliferator gamma coactivator-1α (PGC-1α) as a flow-responsive gene required for endothelial flow alignment in vitro and in vivo. Compared to oscillatory FSS (disturbed flow) or static conditions, laminar FSS (undisturbed flow) increased PGC-1α expression and its transcriptional co-activation. PGC-1α was required for laminar FSS-induced expression of telomerase reverse transcriptase (TERT) in vitro and in vivo via its association with ERRα and KLF4 on the TERT promoter. We found that TERT inhibition attenuated endothelial flow alignment, elongation, and nuclear polarization in response to laminar FSS in vitro and in vivo. Among the flow-responsive genes sensitive to TERT status was heme oxygenase-1 (HMOX1), a gene required for endothelial alignment to laminar FSS. Thus, these data suggest an important role for a PGC-1α-TERT-HMOX1 axis in the endothelial stabilization response to laminar FSS.

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Faculty Opinions recommendation of Fluid Shear Stress Promotes Placental Growth Factor Upregulation in Human Syncytiotrophoblast Through the cAMP-PKA Signaling Pathway.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.726802902.793524002 ◽

2016 ◽

Author(s):

Daniel Vaiman

Keyword(s):

Shear Stress ◽

Growth Factor ◽

Signaling Pathway ◽

Fluid Shear Stress ◽

Placental Growth Factor ◽

Fluid Shear

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P 7 Fluid shear stress promotes placental growth factor upregulation in human syncytiotrophoblast through the camp-pka signaling pathway

Pregnancy Hypertension ◽

10.1016/j.preghy.2017.07.085 ◽

2017 ◽

Vol 9 ◽

pp. 39-40

Author(s):

Edouard Lecarpentier ◽

Anthony Atallah ◽

Jean Guibourdenche ◽

Marylise Hebert-Schuster ◽

Bassam Haddad ◽

...

Keyword(s):

Shear Stress ◽

Growth Factor ◽

Signaling Pathway ◽

Fluid Shear Stress ◽

Placental Growth Factor ◽

Fluid Shear

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Fluid Shear Stress Promotes Placental Growth Factor Upregulation in Human Syncytiotrophoblast Through the cAMP–PKA Signaling Pathway

Hypertension ◽

10.1161/hypertensionaha.116.07890 ◽

2016 ◽

Vol 68 (6) ◽

pp. 1438-1446 ◽

Cited By ~ 9

Author(s):

Edouard Lecarpentier ◽

Anthony Atallah ◽

Jean Guibourdenche ◽

Marylise Hebert-Schuster ◽

Sarah Vieillefosse ◽

...

Keyword(s):

Shear Stress ◽

Growth Factor ◽

Signaling Pathway ◽

Fluid Shear Stress ◽

Placental Growth Factor ◽

Fluid Shear

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PGC1α Regulates the Endothelial Response to Fluid Shear Stress via Telomerase Reverse Transcriptase Control of Heme Oxygenase-1

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/atvbaha.121.317066 ◽

2021 ◽

Author(s):

Shashi Kant ◽

Khanh-Van Tran ◽

Miroslava Kvandova ◽

Amada D. Caliz ◽

Hyung-Jin Yoo ◽

...

Keyword(s):

Shear Stress ◽

Reverse Transcriptase ◽

Heme Oxygenase ◽

Fluid Shear Stress ◽

Heme Oxygenase 1 ◽

Telomerase Reverse Transcriptase ◽

Fluid Shear ◽

Flow Alignment

Objective: Fluid shear stress (FSS) is known to mediate multiple phenotypic changes in the endothelium. Laminar FSS (undisturbed flow) is known to promote endothelial alignment to flow, which is key to stabilizing the endothelium and rendering it resistant to atherosclerosis and thrombosis. The molecular pathways responsible for endothelial responses to FSS are only partially understood. In this study, we determine the role of PGC1α (peroxisome proliferator gamma coactivator-1α)-TERT (telomerase reverse transcriptase)-HMOX1 (heme oxygenase-1) during shear stress in vitro and in vivo. Approach and Results: Here, we have identified PGC1α as a flow-responsive gene required for endothelial flow alignment in vitro and in vivo. Compared with oscillatory FSS (disturbed flow) or static conditions, laminar FSS (undisturbed flow) showed increased PGC1α expression and its transcriptional coactivation. PGC1α was required for laminar FSS-induced expression of TERT in vitro and in vivo via its association with ERRα(estrogen-related receptor alpha) and KLF (Kruppel-like factor)-4 on the TERT promoter. We found that TERT inhibition attenuated endothelial flow alignment, elongation, and nuclear polarization in response to laminar FSS in vitro and in vivo. Among the flow-responsive genes sensitive to TERT status, HMOX1 was required for endothelial alignment to laminar FSS. Conclusions: These data suggest an important role for a PGC1α-TERT-HMOX1 axis in the endothelial stabilization response to laminar FSS.

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