RESUMEN
Mechanotransduction plays a crucial role in vascular biology. One example of this is the local regulation of vascular resistance via flow-mediated dilation (FMD). Impairment of this process is a hallmark of endothelial dysfunction and a precursor to a wide array of vascular diseases, such as hypertension and atherosclerosis. Yet the molecules responsible for sensing flow (shear stress) within endothelial cells remain largely unknown. We designed a 384-well screening system that applies shear stress on cultured cells. We identified a mechanosensitive cell line that exhibits shear stress-activated calcium transients, screened a focused RNAi library, and identified GPR68 as necessary and sufficient for shear stress responses. GPR68 is expressed in endothelial cells of small-diameter (resistance) arteries. Importantly, Gpr68-deficient mice display markedly impaired acute FMD and chronic flow-mediated outward remodeling in mesenteric arterioles. Therefore, GPR68 is an essential flow sensor in arteriolar endothelium and is a critical signaling component in cardiovascular pathophysiology.
Asunto(s)
Mecanotransducción Celular , Interferencia de ARN , Receptores Acoplados a Proteínas G/fisiología , Animales , Materiales Biocompatibles , Calcio/metabolismo , Línea Celular Tumoral , Células Endoteliales/fisiología , Endotelio Vascular/citología , Células HEK293 , Células Endoteliales de la Vena Umbilical Humana , Humanos , Concentración de Iones de Hidrógeno , Arterias Mesentéricas/fisiología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Óxido Nítrico/metabolismo , ARN Interferente Pequeño/metabolismo , Receptores Acoplados a Proteínas G/genética , Resistencia al Corte , Estrés Mecánico , Resistencia VascularRESUMEN
BACKGROUND: Appendicularia consists of approximately 70 purely marine species that belong to Tunicata the probable sister taxon to Craniota. Therefore, Appendicularia plays a pivotal role for our understanding of chordate evolution. In addition, appendicularians are an important part of the epipelagic marine plankton. Nevertheless, little is known about appendicularian species, especially from deeper water. RESULTS: Using µCT, scanning electron microscopy, and digital 3D-reconstruction techniques we describe three pairs of complex oral sensory organs in the mesopelagic appendicularian Bathochordaeus stygius. The oral sensory organs are situated at the anterior and lateral margin of the mouth and inside the mouth cavity. A single organ consists of 22-90 secondary receptor cells that project apical cilia through a narrow hole in the epidermis. The receptor cells are innervated by branches of the second brain nerve. CONCLUSIONS: Based on position, morphology, and innervation we suggest that the oral sensory organs are homologues of the coronal organs in other tunicates. We discuss the hypothesized homology of coronal organs and the lateral line system of primary aquatic vertebrates. The complex oral sensory organs of B. stygius are unique in tunicates and could be adaptations to the more muffled environment of the mesopelagic.