BACKGROUND AND PURPOSE Despite the observation of synergistic interactions between the urotensinergic and angiotensinergic systems, the interplay between the urotensin II receptor (hUT) and the angiotensin II type 1 receptor (hAT1R) in regulating cellular signaling under physiological and pathophysiological conditions remains incompletely understood. Notably, the interaction between hUT and hAT1R could engender reciprocal allosteric modulations of their signaling signatures, defining a unique role for these complexes in cardiovascular physiology and pathophysiology. EXPERIMENTAL APPROACH The physical interaction between hUT and hAT1R receptors was evaluated by co-immunoprecipitation, bioluminescence resonance energy transfer (BRET) and FlAsH BRET-based conformational biosensors. To analyze how this functional interaction regulated proximal and distal hUT-associated signaling pathways, we used BRET-based signaling biosensors and western blots to profile pathway-specific signaling in HEK 293 cells expressing hUT, hAT1R or both. KEY RESULTS We observed that hUT-hAT1R heterodimers triggered distinct signalling outcomes, in particular Gq/ G13/Gi/DAG/-arrestin-1/ERK1/2, compared to their respective parent receptors alone. Notably, co-transfection of hUT and hAT1R slightly potentiated hUII-induced Gq activation but significantly reduced the potency and efficacy of Ang II to mediate Gq activation. Using a FlAsH-walk approach, we observed that the presence of unliganded hUT altered conformational dynamics of hAT1R but that addition of hUII or URP did not produce further modulations. CONCLUSION Assembly of hUT with hAT1R might be important for allosteric modulation of outcomes associated with specific hardwired signaling complexes in healthy and disease states. Our work validates such complexes as potential targets to promote the design of compounds that modulate heterodimer function selectively.