Neuropilin-1 Modulates Vascular Permeability through Juxtacrine Regulation of Endothelial Adherens Junctions

Core Concepts

Neuropilin-1 expression in perivascular cells acts as a tissue-specific modifier of endothelial VEGFA/VEGFR2 signaling and vascular leakage.

Abstract

The study investigates the role of neuropilin-1 (NRP1) in regulating VEGFA-mediated vascular permeability. Using endothelial-specific and global NRP1 knockout mouse models, the authors find that NRP1 has an organotypic function in modulating VEGFA/VEGFR2 signaling and vascular leakage. Key highlights: In the ear skin, loss of endothelial NRP1 increases VEGFA-induced vascular leakage, suggesting NRP1 negatively regulates VEGFR2 signaling. In the trachea and back skin, loss of endothelial NRP1 decreases VEGFA-induced vascular leakage, indicating a positive regulatory role. Global NRP1 knockout suppresses VEGFA-induced vascular leakage in the ear skin, implicating perivascular NRP1 as a juxtacrine co-receptor of VEGFA. The ratio of NRP1 expression between endothelial cells and perivascular cells differs between vascular beds, which may explain the organotypic effects. NRP1 distribution modifies VEGFR2 signaling upstream of vascular leakage, with perivascular NRP1 potentiating VEGFR2 Y949 phosphorylation and VE-cadherin disruption in the ear skin. The authors conclude that the relative expression of NRP1 between endothelial cells and perivascular cells acts as a tissue-specific modifier of endothelial VEGFA/VEGFR2 signaling and vascular barrier integrity.

Stats

"NRP1 protein levels were reduced by 75% in the lungs of Nrp1 iECKO mice compared to controls." "Loss of endothelial NRP1 increased VEGFA-induced vascular leakage sites by 2-fold in the ear skin of Nrp1 iECKO mice compared to controls." "Loss of endothelial NRP1 decreased VEGFA-induced vascular leakage by ~75% in the trachea and back skin of Nrp1 iECKO mice compared to controls." "Global loss of NRP1 in Nrp1 iKO mice reduced VEGFA-induced vascular leakage by ~75% in the trachea and back skin compared to controls."

Quotes

"NRP1 has been shown to have the ability to act in a juxtacrine manner." "Importantly, NRP1 was more abundant in perivascular cells of the ear skin than back skin." "Collectively, these data reveal that the relative expression levels of NRP1 between perivascular cells and ECs acts as a tissue-specific modifier of EC VEGFA/VEGFR2 signalling upstream of vascular leakage."

Key Insights Distilled From

Neuropilin-1 controls vascular permeability through juxtacrine regulation of endothelial adherens junctions

by Pal,S., Su,Y... at www.biorxiv.org 01-24-2024

https://www.biorxiv.org/content/10.1101/2024.01.23.576785v1

Deeper Inquiries

How might the differential expression and distribution of NRP1 in perivascular cells versus endothelial cells be regulated in different vascular beds?

The regulation of NRP1 expression and distribution in perivascular cells versus endothelial cells in different vascular beds can be influenced by various factors. One key factor is the microenvironment of the specific vascular bed, which can dictate the expression levels of NRP1 in perivascular cells. For example, the signaling molecules present in the local environment, such as growth factors or cytokines, can regulate NRP1 expression. Additionally, the interaction between perivascular cells and endothelial cells can also impact NRP1 expression. Moreover, the differential expression of NRP1 in perivascular cells versus endothelial cells may be regulated by epigenetic mechanisms. Epigenetic modifications, such as DNA methylation or histone modifications, can control the expression of NRP1 in a cell-specific manner. Furthermore, transcription factors that are specific to perivascular cells or endothelial cells may regulate the expression of NRP1 in these cell types. Overall, the differential expression and distribution of NRP1 in perivascular cells versus endothelial cells in different vascular beds are likely regulated by a combination of microenvironmental cues, cell-cell interactions, and epigenetic mechanisms.

What are the potential therapeutic implications of targeting the NRP1-VEGFR2 axis in diseases characterized by vascular hyperpermeability, such as age-related macular degeneration or cancer?

Targeting the NRP1-VEGFR2 axis in diseases characterized by vascular hyperpermeability, such as age-related macular degeneration or cancer, holds significant therapeutic potential. By modulating the interaction between NRP1 and VEGFR2, it may be possible to regulate vascular permeability and potentially reduce disease progression. In age-related macular degeneration, where abnormal vessel growth and increased vascular permeability contribute to disease pathology, targeting the NRP1-VEGFR2 axis could help normalize vascular function and reduce leakage. This could potentially slow down disease progression and preserve vision in affected individuals. In cancer, where increased angiogenesis and vascular hyperpermeability are hallmarks of tumor growth and metastasis, targeting NRP1-VEGFR2 interactions could inhibit tumor angiogenesis and reduce tumor vascular permeability. This could lead to improved drug delivery to the tumor site and enhance the efficacy of anti-cancer therapies. Overall, targeting the NRP1-VEGFR2 axis in diseases characterized by vascular hyperpermeability offers a promising therapeutic strategy to modulate vascular function, reduce leakage, and potentially improve patient outcomes.

Could the juxtacrine interactions between NRP1 and VEGFR2 play a role in other vascular processes beyond permeability, such as angiogenesis or vascular remodeling?

The juxtacrine interactions between NRP1 and VEGFR2 have the potential to play a significant role in various vascular processes beyond permeability, including angiogenesis and vascular remodeling. These interactions can modulate VEGFR2 signaling and downstream pathways, influencing the behavior of endothelial cells and perivascular cells in different vascular contexts. In angiogenesis, the juxtacrine interactions between NRP1 and VEGFR2 can regulate the sprouting and branching of new blood vessels. By modulating VEGFR2 signaling in a juxtacrine manner, NRP1 can influence the guidance of endothelial cells during angiogenic processes, promoting or inhibiting vessel growth in response to specific cues. In vascular remodeling, the juxtacrine interactions between NRP1 and VEGFR2 may impact the maintenance and adaptation of blood vessels in response to physiological or pathological stimuli. By altering VEGFR2 signaling dynamics through juxtacrine interactions, NRP1 can regulate processes such as vessel maturation, stabilization, or regression in different vascular beds. Overall, the juxtacrine interactions between NRP1 and VEGFR2 have the potential to play a multifaceted role in various vascular processes, including angiogenesis and vascular remodeling, by modulating VEGFR2 signaling and influencing cellular behavior in a context-dependent manner.