Background Whether biomechanical force on the heart can induce exosome secretion to modulate cardiovascular function is not known. We investigated the secretion and activity of exosomes containing a key receptor in cardiovascular function, the Angiotensin II Type I Receptor (AT1R). Methods and Results Exosomes containing AT1Rs were isolated from the media overlying AT1R-overexpressing cells exposed to osmotic stretch and from sera of mice undergoing cardiac pressure overload. The presence of AT1Rs in exosomes was confirmed by both electron microscopy and radioligand receptor binding assays, and shown to require β-arrestin2, a multifunctional adaptor protein essential for receptor trafficking. We show that functional AT1Rs are transferred via exosomes in an in vitro model of cellular stretch. Using mice with global and cardiomyocyte conditional deletion of β-arrestin2, we show that under conditions of in vivo pressure overload the cellular source for the exocytosis of exosomes containing AT1R is the cardiomyocyte. Exogenous administered AT1R-enriched exosomes target cardiomyocytes, skeletal myocytes and mesenteric resistance vessels, and is sufficient to confer blood pressure responsiveness to angiotensin II infusion in AT1R knockout mice. Conclusions This work reveals that AT1R-enriched exosomes are released from the heart under conditions of in vivo cellular stress to likely modulate vascular responses to neurohormonal stimulation. In the context of the whole organism, the concept of G protein-coupled receptor trafficking should consider circulating exosomes as part of the reservoir of functional AT1Rs.

We have structurally evaluated β-Ga2O3 crystals grown by edge-defined film-fed growth process using etch pitting, focused ion beam scanning ion microscopy, transmission electron microscopy, and related techniques. We found three types of defects: arrays of edge dislocations corresponding to etch pit arrays on -oriented wafers, platelike nanopipes corresponding to etch pits revealed on the (010)-oriented wafers, and twins including twin lamellae.

The β1 adrenergic receptor (β1AR) is recognized as a classical Gαs-coupled receptor. Agonist binding not only initiates G protein-mediated signaling but also signaling through the multifunctional adapter protein β-arrestin. Some βAR ligands, such as carvedilol, stimulate βAR signaling preferentially through β-arrestin, a concept known as β-arrestin-biased agonism. Here, we identify a signaling mechanism, unlike that previously known for any Gαs-coupled receptor, whereby carvedilol induces the transition of the β1AR from a classical Gαs-coupled receptor to a Gαi-coupled receptor stabilizing a distinct receptor conformation to initiate β-arrestin-mediated signaling. Recruitment of Gαi is not induced by any other βAR ligand screened, nor is it required for β-arrestin-bias activated by the β2AR subtype of the βAR family. Our findings demonstrate a previously unrecognized role for Gαi in β1AR signaling and suggest that the concept of β-arrestin-bias may need to be refined to incorporate the selective bias of receptors towards distinct G protein subtypes.