Abstract: TH-OR75
Key Role of Neuroendothelial Cells in Renal Blood Flow Regulation
Session Information
- Hypertension and CVD: Research Advances
October 24, 2024 | Location: Room 5, Convention Center
Abstract Time: 04:50 PM - 05:00 PM
Category: Hypertension and CVD
- 1601 Hypertension and CVD: Basic
Authors
- Gyarmati, Georgina, University of Southern California, Los Angeles, California, United States
- Becerra Calderon, Alejandra, University of Southern California, Los Angeles, California, United States
- Izuhara, Audrey, University of Southern California, Los Angeles, California, United States
- Deepak, Sachin K., University of Southern California, Los Angeles, California, United States
- Trogen, Greta H., University of Southern California, Los Angeles, California, United States
- Peti-Peterdi, Janos, University of Southern California, Los Angeles, California, United States
Background
Transcriptomic studies identified many vascular endothelial cell (EC) subtypes in multiple organs including the kidney. However, their functions are incompletely understood. Our recent studies discovered and characterized the novel minority EC subtype named neuro-endothelial cells (NECs) with endothelial and neuronal characteristics. NECs were found exclusively in small resistance arterioles of the three most metabolically active organs that show the best blood flow regulation, with the highest density in the brain and retina> kidney >heart. Here we hypothesized that NECs are key players in organ blood flow regulation.
Methods
A comprehensive NEC research toolbox including high-resolution transcriptome analysis of mouse brain and kidney ECs, transgenic mouse models, and intravital multiphoton microscopy (MPM) were used.
Results
Single-cell transcriptome analysis demonstrated that in contrast to other ECs, NECs highly express several traditional (e.g., Nos1, Adra2c, Vegfc, Angpt1, Egfl8) and novel (e.g., Cytl1, Mgp, Gkn3) vasoactive and angiogenic factors. Gene Set Enrichment Analysis of the top NEC genes suggested the role of NECs in blood vessel diameter maintenance and vasculature development. MPM of intact kidney arterioles revealed robust NEC-specific calcium responses to acute norepinephrine challenge suggesting the role of NEC adrenoceptors in stress-induced redistribution of regional blood flow. MPM imaging of NEC-Ai27 mouse model revealed that acute optogenetic stimulation of NECs led to rapid vasodilation (D/D0=152+/-7%, p<0.0001). This effect was blunted in mice pretreated with the Nos1 specific inhibitor 7NI suggesting the main role of NEC neuronal nitric oxide synthase in the maintenance of organ blood flow. In contrast, the acute optogenetic inhibition of single NECs in NEC-Ai39 mouse model resulted in imminent vasoconstriction (D/D0=75+/-4%, p<0.01). Further, treatment with Cytl1, a novel angiogenic factor highly enriched in NECs, resulted in EC calcium responses and vasodilation acutely, and in increased capillary density and clonal EC remodeling chronically in Cdh5-GCaMP and Confetti mice, respectively.
Conclusion
In conclusion, the newly discovered NEC molecular mechanisms may play a major role in organ blood flow regulation and may be targeted in future therapeutic development for kidney diseases.
Funding
- NIDDK Support