Regulation of Collecting Lymphatic Vessel Contractile Function by TRPV4 Channels.

Area of Science:

• Vascular Biology
• Immunology
• Cellular Physiology

Background:

• Dysregulation of TRPV4 (transient receptor potential vanilloid type 4) signaling is linked to inflammation and fibrosis in lymphatic diseases.
• The precise role and expression of TRPV4 in lymphatic vessels remain largely uncharacterized.

Purpose of the Study:

• To investigate the expression and function of TRPV4 channels in lymphatic endothelial cells and peri-lymphatic myeloid cells.
• To elucidate the mechanisms underlying TRPV4-mediated lymphatic contractile dysregulation.

Main Methods:

• Single-cell RNA sequencing of mouse collecting lymphatic vessels.
• Utilized a novel Trpv4 conditional knockout mouse model (Trpv4fx/fx) with Prox1-CreER T2 and LysM-Cre lines.
• Functional assays on isolated lymphatics, including calcium imaging, and analysis of human lymphedema biopsies.

Main Results:

• Trpv4 expression was high in lymphatic endothelial cells and LYVE1+ macrophages.
• Breast cancer-related lymphedema showed increased LYVE1 and TRPV4 co-expressing macrophages.
• TRPV4 activation caused multiphasic contractile dysregulation, involving vasospasm (TXA2R-mediated) and vasodilation (NO-mediated).

Conclusions:

• A novel mechanism of lymphatic contractile dysregulation involves crosstalk between TRPV4+ myeloid cells and lymphatic cells.
• TRPV4 channels play a significant role in lymphatic dysfunction and inflammation-associated conditions like secondary lymphedema.