Their selective deletion has been useful to investigate the role of primary cilia in many cells. Several intraflagellar transport proteins, including intraflagellar transport protein 88 (IFT88), specific kinesin motors like KIF3a, and other structural components like ARL13b, are essential for formation and maintenance of primary cilia ( Nonaka et al., 1998 Taulman et al., 2001 Hori et al., 2008). The ciliary axoneme is surrounded by the ciliary membrane, a specialized compartment in which many receptors, ion channels, and transporter proteins are embedded, where they recruit second messengers and effectors ( Satir et al., 2010). The primary cilium extends from the membrane of the cell and is stabilized by a microtubule scaffold known as the axoneme. Among them, the primary cilium has been shown to bend in response to blood flow and to be required for flow sensing, thus controlling endothelial function in both normal and pathological conditions ( Goetz et al., 2014 Dinsmore and Reiter, 2016). Many structures and receptors have been identified as flow sensors in ECs ( Traub and Berk, 1998 Baeyens et al., 2016a). Vascular regression has been shown to rely on axial polarization of ECs against the direction of blood flow and their consequent migration from poorly perfused vessels into well-perfused neighboring segments, thus removing superfluous connections and reinforcing vessels that experience higher shear stress ( Franco et al., 2015, 2016). However, how ECs sense and transduce mechanical signals during vascular remodeling to achieve a balanced network of blood vessels is still poorly understood ( Dolan et al., 2013). Adaptation of ECs to flow is critical for the development and maintenance of a well-functioning cardiovascular system for example, in adult mice flow-sensing through VEGFR3 controls vessel caliber ( Baeyens et al., 2015). Interestingly, ECs are able to sense small variations in the direction, magnitude, and regularity of blood flow–induced shear stress ( Wang et al., 2013 Givens and Tzima, 2016) and respond to such changes by influencing vasculature remodeling ( Culver and Dickinson, 2010 Baeyens et al., 2016a). Endothelial cells (ECs) in particular are under constant mechanical strains exerted by blood flow. Thus, excessive remodeling and the removal of all nonperfused vessels carry long-term risk, whereas too little remodeling impedes vascular function.Ĭells need to respond appropriately to mechanical cues to ensure healthy tissue development and homeostasis. Nevertheless, the maintenance of redundant collateral vessels, despite being poorly perfused in normal physiology, is critical for recovery after injury in this context, superfluous connections become active, increase in size, and substitute damaged vessels ( Liu et al., 2014). Mice with genetic inactivation of factors involved in vascular remodeling die during midgestation ( Potente et al., 2011), demonstrating the critical importance of remodeling. A primary vascular plexus initially expands by sprouting angiogenesis ( Isogai et al., 2003 Potente et al., 2011) followed by vascular remodeling to adapt vessel organization, shape, and size in its course, superfluous and inefficient connections are pruned away by active regression ( Franco et al., 2015). We propose that BMP9 signaling cooperates with the primary cilia at low flow to keep immature vessels open before high shear stress–mediated remodeling.Įfficient oxygen and nutrient supply through the formation of a hierarchically branched network of blood vessels is essential for vertebrate development. Molecularly, we identify that primary cilia endow endothelial cells with strongly enhanced sensitivity to bone morphogenic protein 9 (BMP9), selectively under low flow. IFT88 mutant cells lacking primary cilia displayed reduced polarization against blood flow, selectively at low and intermediate flow levels, and have a stronger migratory behavior. Inducible genetic deletion of the essential cilia component intraflagellar transport protein 88 (IFT88) in endothelial cells caused premature and random vessel regression without affecting proliferation, cell cycle progression, or apoptosis. Here, we show that endothelial cells in the developing mouse retina form and use luminal primary cilia to stabilize vessel connections selectively in parts of the remodeling vascular plexus experiencing low and intermediate shear stress. How endothelial cells read and interpret flow-derived signals is poorly understood. Blood flow shapes vascular networks by orchestrating endothelial cell behavior and function.
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