Abstract Body (Do not enter title and authors here): Background: Vascular smooth muscle (VSM) contractility is central to maintaining vascular tone and blood pressure. Angiotensin II (Ang II) is a central hormone in the renin-angiotensin system and a major driver of vasoconstriction and hypertension. Although Neuropilin-1 (NRP1), a transmembrane receptor, has well-known functions in vascular development, its role in adult VSM physiology and Ang II -mediated vascular responses remains poorly defined.
Objective: To investigate the role of NRP1 in regulating aortic contractility, blood pressure dynamics, and Ang II signaling in adult VSM.
Methods: An inducible smooth muscle-specific Nrp1 knockout mouse model (SM22aCre^ERT2; Nrp1^fl/fl) was used to assess changes in blood pressure, vascular tone, cardiac function, and molecular signaling under basal conditions and in responses to Ang II infusion. Contractility and levels of phosphorylated myosin light chain (p-MLC) were analyzed ex vivo in isolated aortas with and without Ang II treatment. Ang II receptor expression (AGTR1, AGTR2) was evaluated by mRNA and protein analysis, where applicable.
Results: Deletion of Nrp1 in VSM caused a transient rise in systolic blood pressure and aortic contractility, both peaking within 2 weeks and normalizing by weeks 4–6, with stable blood pressure for 6 months. In contrast, p-MLC remained persistently elevated despite reduced AGTR1/2, suggesting involvement of non-canonical Ang II pathways. NRP1 may regulate tone via direct effects on contractile machinery or increased sensitivity to other vasoconstrictors. Compensation over time, possibly vascular or cardiac, is under investigation, though cardiac function remained unchanged.
Following Ang II infusion, control mice developed hypertension, while Nrp1-deficient mice remained normotensive. This protection was associated with blunted Ang II-induced p-MLC activation and upregulation of AGTR1 and AGTR2 in knockout aortas, highlighting the importance of NRP1 in facilitating Ang II–mediated contractile signaling and indicating a context-dependent compensatory mechanism.
Conclusions: NRP1 plays a critical role in both basal vascular tone and Ang II-mediated contractile responses. Its deletion alters Ang II receptor expression in a context-dependent manner and prevents Ang II-induced hypertension. These findings support NRP1 as a key regulator of vascular function and a potential therapeutic target in hypertension and related cardiovascular diseases.