betekintés - Computational Biology - # Aquaporin Function in Endothelial Cell Migration and Angiogenesis

Aquaporin-Mediated Water Influx Promotes Endothelial Tip Cell Migration and Sprouting Angiogenesis in Zebrafish

Q: How do other ion transporters and channels work in concert with Aquaporins to regulate the osmotic gradient and hydrostatic pressure driving endothelial cell migration and angiogenesis?

In addition to Aquaporins, several ion transporters and channels work in concert to regulate the osmotic gradient and hydrostatic pressure driving endothelial cell migration and angiogenesis. These ion transporters and channels play crucial roles in maintaining cell volume, membrane potential, and ion homeostasis, which are essential for cell migration and angiogenesis. Some key players include: Sodium-Potassium Pump (Na+/K+ ATPase): The Na+/K+ ATPase maintains the electrochemical gradient by pumping sodium out of the cell and potassium into the cell. This gradient is essential for maintaining cell volume and regulating water movement. Chloride Channels: Chloride channels play a role in regulating cell volume and membrane potential. They work in conjunction with Aquaporins to maintain osmotic balance and water movement in endothelial cells. Sodium-Hydrogen Exchanger (NHE): NHE proteins regulate intracellular pH and cell volume by exchanging sodium ions for protons. They are involved in cell migration and angiogenesis by modulating the osmotic gradient and pH balance. Potassium Channels: Potassium channels regulate membrane potential and cell volume, influencing cell migration and angiogenesis. They work in coordination with Aquaporins to maintain ion balance and water movement in endothelial cells. Calcium Channels: Calcium channels play a role in cell migration and angiogenesis by regulating cytoskeletal dynamics and cell signaling pathways. They interact with Aquaporins to modulate water permeability and cell volume changes during migration. By working together, these ion transporters and channels help regulate the osmotic gradient, hydrostatic pressure, and ion balance necessary for endothelial cell migration and angiogenesis. Disruption in the coordinated function of these transporters and channels can impact cell behavior and vascular development.

Q: Could modulating Aquaporin function be a potential therapeutic strategy to promote or inhibit angiogenesis in the context of diseases like cancer, ischemia, or macular degeneration?

Modulating Aquaporin function could indeed be a promising therapeutic strategy to regulate angiogenesis in various disease contexts such as cancer, ischemia, and macular degeneration. Here's how Aquaporin modulation could be utilized: Cancer: In cancer, tumor growth and metastasis rely on angiogenesis to supply nutrients and oxygen. By targeting Aquaporins involved in endothelial cell migration and sprouting angiogenesis, it may be possible to inhibit tumor angiogenesis and limit tumor progression. Inhibiting specific Aquaporins could disrupt the water influx necessary for endothelial cell migration, thereby hindering tumor vascularization. Ischemia: In conditions like ischemia, where there is inadequate blood supply to tissues, promoting angiogenesis can help restore blood flow and improve tissue perfusion. Enhancing Aquaporin function to increase water influx and hydrostatic pressure in endothelial cells could potentially stimulate angiogenesis and facilitate the formation of new blood vessels to restore blood flow to ischemic tissues. Macular Degeneration: In diseases like age-related macular degeneration (AMD), abnormal angiogenesis can lead to vision loss. Targeting Aquaporins involved in endothelial cell migration and vessel formation could help regulate pathological angiogenesis in the eye. Modulating Aquaporin function may offer a way to inhibit abnormal blood vessel growth and preserve vision in AMD patients. By selectively modulating Aquaporin function, either through pharmacological agents or gene therapy approaches, it may be possible to fine-tune angiogenesis in disease settings to either promote or inhibit blood vessel formation as needed. Further research into the specific roles of different Aquaporins in angiogenesis and their potential as therapeutic targets is warranted to explore their clinical utility in disease management.

Alapfogalmak

Aquaporin-mediated water influx into endothelial tip cells generates hydrostatic pressure that, together with actin polymerization, drives membrane protrusions and cell migration during sprouting angiogenesis.

Kivonat

The study investigates the role of aquaporins, which are transmembrane water channels, in regulating endothelial cell (EC) migration and sprouting angiogenesis in the zebrafish.

Key findings:

The aquaporin genes aqp1a.1 and aqp8a.1 are differentially expressed in tip and stalk cells of newly formed vascular sprouts, with aqp1a.1 enriched in tip cells and aqp8a.1 in stalk cells.
VEGFR2 signaling upregulates the expression of aqp1a.1 and aqp8a.1 in ECs.
Aqp1a.1 and Aqp8a.1 proteins localize to the leading edge of migrating tip cells, suggesting a role in promoting water influx.
Zebrafish lacking both Aqp1a.1 and Aqp8a.1 show delayed tip cell emergence from the dorsal aorta, reduced tip cell volume, decreased filopodia formation and stability, and impaired tip cell migration, leading to defective sprouting angiogenesis.
The combined loss of Aqp1a.1/Aqp8a.1 and inhibition of actin polymerization results in a greater impairment of EC migration and vessel formation compared to either perturbation alone.
The findings demonstrate that endothelial tip cells employ two concurrent mechanisms - actin polymerization and Aquaporin-mediated water influx - to generate membrane protrusions and drive robust cell migration during angiogenesis.

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biorxiv.org

Statisztikák

"Tip cells of newly formed vascular sprouts express higher levels of aqp1a.1 compared to adjacent endothelial cells in the dorsal aorta at 20 hpf."
"In 78% of intersegmental vessels analyzed, aqp8a.1 mRNA is more highly expressed in stalk cells than tip cells at 22 hpf."
"Inhibition of VEGFR2 activity suppresses aqp1a.1 mRNA expression by 52% after 6 hours and by 40% after 24 hours, and aqp8a.1 mRNA expression by 17% after 6 hours and 93% after 24 hours."
"Tip cell volume is significantly decreased by 24% in aqp1a.1rk28/rk28;aqp8a1rk29/rk29 mutants compared to wildtype."
"The growth rate of actin bundles in filopodia is reduced by 47% in aqp1a1rk28/rk28;aqp8a1rk29/rk29 mutants compared to wildtype."
"The length of intersegmental vessels is decreased by 58% in aqp1a1rk28/rk28;aqp8a1rk29/rk29 mutants compared to wildtype, and by 34% in aqp1a1rk28/rk28 and 39% in aqp8a1rk29/rk29 single mutants."

Idézetek

"Aqp1a.1 and Aqp8a.1 proteins are enriched at the leading front of migrating tip cells, suggesting that Aqp1a.1 and Aqp8a.1 may promote localized water flux at the migrating edge of tip cells."
"In the absence of both Aqp1a.1 and Aqp8a.1 function, there is delayed tip cell protrusion from the dorsal aorta, decreased tip cell migration and increased occurrence of truncated intersegmental vessels at 3 dpf."
"When both actin polymerization and Aquaporin-mediated water influx are perturbed, there is a greater impairment in endothelial cell migration and sprouting angiogenesis."

Főbb Kivonatok

Combined forces of hydrostatic pressure and actin polymerization drive endothelial tip cell migration and sprouting angiogenesis

by Kondrychyn,I... : www.biorxiv.org 05-20-2024

https://www.biorxiv.org/content/10.1101/2024.05.20.594949v1

Mélyebb kérdések

How do the subcellular localization and trafficking of Aqp1a.1 and Aqp8a.1 proteins in endothelial cells change in response to different developmental or environmental cues?

The subcellular localization and trafficking of Aqp1a.1 and Aqp8a.1 proteins in endothelial cells can be dynamically regulated in response to various developmental or environmental cues. These cues can include growth factors, cytokines, mechanical forces, and changes in osmotic pressure.

Developmental Cues: During development, the expression and localization of Aquaporins may change in response to signaling pathways involved in vascular development. For example, VEGFR2 signaling has been shown to upregulate the expression of aqp1a.1 and aqp8a.1 in endothelial cells. This suggests that during angiogenesis, the activation of VEGFR2 by VEGFA can lead to increased expression and localization of Aquaporins at the leading edge of migrating tip cells.

Environmental Cues: Environmental factors such as hypoxia, inflammation, and shear stress can also influence the subcellular localization of Aquaporins. For instance, in response to hypoxia, Aquaporins may translocate to the plasma membrane to facilitate water influx and maintain cell volume homeostasis. Inflammatory cytokines can also modulate Aquaporin expression and localization to regulate water transport in endothelial cells.

Mechanical Forces: Mechanical cues, such as fluid shear stress, can impact Aquaporin localization and function in endothelial cells. Shear stress has been shown to regulate the expression and subcellular distribution of Aquaporins, potentially affecting water permeability and cell migration in response to fluid flow.

Osmotic Gradients: Changes in osmotic gradients can directly influence the trafficking of Aquaporins. High osmolarity conditions may lead to increased translocation of Aquaporins to the plasma membrane to facilitate water transport, while low osmolarity conditions may result in internalization of Aquaporins to regulate water permeability.

In summary, the subcellular localization and trafficking of Aqp1a.1 and Aqp8a.1 proteins in endothelial cells can be dynamically modulated by various developmental and environmental cues to regulate water influx, cell volume, and migration during angiogenesis.

How do other ion transporters and channels work in concert with Aquaporins to regulate the osmotic gradient and hydrostatic pressure driving endothelial cell migration and angiogenesis?

In addition to Aquaporins, several ion transporters and channels work in concert to regulate the osmotic gradient and hydrostatic pressure driving endothelial cell migration and angiogenesis. These ion transporters and channels play crucial roles in maintaining cell volume, membrane potential, and ion homeostasis, which are essential for cell migration and angiogenesis. Some key players include:

Sodium-Potassium Pump (Na+/K+ ATPase): The Na+/K+ ATPase maintains the electrochemical gradient by pumping sodium out of the cell and potassium into the cell. This gradient is essential for maintaining cell volume and regulating water movement.

Chloride Channels: Chloride channels play a role in regulating cell volume and membrane potential. They work in conjunction with Aquaporins to maintain osmotic balance and water movement in endothelial cells.

Sodium-Hydrogen Exchanger (NHE): NHE proteins regulate intracellular pH and cell volume by exchanging sodium ions for protons. They are involved in cell migration and angiogenesis by modulating the osmotic gradient and pH balance.

Potassium Channels: Potassium channels regulate membrane potential and cell volume, influencing cell migration and angiogenesis. They work in coordination with Aquaporins to maintain ion balance and water movement in endothelial cells.

Calcium Channels: Calcium channels play a role in cell migration and angiogenesis by regulating cytoskeletal dynamics and cell signaling pathways. They interact with Aquaporins to modulate water permeability and cell volume changes during migration.

By working together, these ion transporters and channels help regulate the osmotic gradient, hydrostatic pressure, and ion balance necessary for endothelial cell migration and angiogenesis. Disruption in the coordinated function of these transporters and channels can impact cell behavior and vascular development.

Could modulating Aquaporin function be a potential therapeutic strategy to promote or inhibit angiogenesis in the context of diseases like cancer, ischemia, or macular degeneration?

Modulating Aquaporin function could indeed be a promising therapeutic strategy to regulate angiogenesis in various disease contexts such as cancer, ischemia, and macular degeneration. Here's how Aquaporin modulation could be utilized:

Cancer: In cancer, tumor growth and metastasis rely on angiogenesis to supply nutrients and oxygen. By targeting Aquaporins involved in endothelial cell migration and sprouting angiogenesis, it may be possible to inhibit tumor angiogenesis and limit tumor progression. Inhibiting specific Aquaporins could disrupt the water influx necessary for endothelial cell migration, thereby hindering tumor vascularization.

Ischemia: In conditions like ischemia, where there is inadequate blood supply to tissues, promoting angiogenesis can help restore blood flow and improve tissue perfusion. Enhancing Aquaporin function to increase water influx and hydrostatic pressure in endothelial cells could potentially stimulate angiogenesis and facilitate the formation of new blood vessels to restore blood flow to ischemic tissues.

Macular Degeneration: In diseases like age-related macular degeneration (AMD), abnormal angiogenesis can lead to vision loss. Targeting Aquaporins involved in endothelial cell migration and vessel formation could help regulate pathological angiogenesis in the eye. Modulating Aquaporin function may offer a way to inhibit abnormal blood vessel growth and preserve vision in AMD patients.

By selectively modulating Aquaporin function, either through pharmacological agents or gene therapy approaches, it may be possible to fine-tune angiogenesis in disease settings to either promote or inhibit blood vessel formation as needed. Further research into the specific roles of different Aquaporins in angiogenesis and their potential as therapeutic targets is warranted to explore their clinical utility in disease management.