the circulatory system consists of a fluid ( blood ) , a pump ( the heart ) , and the vessels through which the blood circulates . vertebrates also have a parallel system of lymphatic vessels that drain excess fluid from the tissues and return it to the blood . these structures are lined by a specialized epithelium , the endothelium , which is supported by mural cells ( pericytes in capillaries and smooth muscle cells in arteries and veins ) and extracellular matrix . flowing blood and lymph exert a frictional force parallel to the endothelial surface termed fluid shear stress ( fss ) . fss magnitude is directly proportional to the fluid velocity and viscosity and inversely proportional to the vessel diameter . typical magnitudes in human blood vessels are between 0.5 and 5 pa ( lipowsky et al . , 1978 ) and 10 times lower in lymphatic vessels ( dixon et al . , 2006 ) . for comparison , typical traction forces from endothelial cells ( ecs ) in vitro are 100 pa ( krishnan et al . , 2011 ) , while circumferential stretch of the vessel wall during the cardiac cycle can be > 1000 pa ( haga et al . , 2007 ) . blood and lymph flow are also pulsatile , with distinct characteristics depending on location and conditions ( feaver et al . , 2013 ) . flow can be laminar and unidirectional ( i.e. , flow smoothly ) ; laminar with backflow ( oscillatory ) and multidirectional ( different angles , including perpendicular ) ; or turbulent ( i.e. , chaotic ) . oscillatory flow is prominent in lymphatic vessels ( dixon et al . , 2006 ) ; multidirectional flows occur at vessel bifurcations or other irregularities ( zhao et al . , 2000 ) , while true turbulence occurs just after the aortic valve or in more severe irregularities associated with disease ( glan et al . , 2012 ) . despite its comparatively low magnitude , fss is a major determinant of both developmental and postnatal remodeling of vasculature and lymphatics . in this review , we discuss recent views on the different mechanisms of flow sensing and their roles in physiology and disease . while flow sensing has been attributed to different mechanosensors , including g protein  coupled receptors , glycocalyx , and primary cilium and ion channels ( hahn and schwartz , 2009 ) , the best - studied fss mechanoreceptor is the endothelial - specific junctional complex comprising pecam1 , ve - cadherin , vegfr2 ( tzima et al . , 2005 ) , and more recently vegfr3 ( coon et al . , 2015 ) ( figure 1a ) . pulling on these receptors with magnetic beads demonstrated direct mechanotransduction by pecam1 ( tzima et al . measurements using fluorescence - based tension sensors confirmed that flow induced an increase in force on pecam1 , unexpectedly mediated by de novo connection of pecam1 to the vimentin cytoskeleton and transmission of force from myosin ( conway et al . , 2013 ) . ve - cadherin bears force constitutively but does not transduce forces from flow , instead functioning as an adaptor . this function is mediated at least in part by the binding to vegf receptors 2 and 3 through their respective transmembrane domains ( coon et al . , 2015 ) . our current model for mechanotransduction is that flow first acts on an as yet unidentified upstream sensor , which triggers cytoskeletal association of pecam1 and transmission of myosin - derived force to this molecule ( conway et al . , 2013 ) ; force on pecam1 triggers activation of a src family kinase , probably fyn ( chiu et al . , 2008 ) ; in the presence of ve - cadherin , src phosphorylates and transactivates vegfrs , which mediate downstream signaling ( figure 1a ) ( a ) endothelial mechanosensitive junctional complex . conceptual model for the assembly of the junctional mechanosensory complex . vegf receptors ( both vegfr2 and vegfr3 ) and ve - cadherin associate through their transmembrane domains ( tmds ) within the plasma membrane ( pm ) . fss triggers force on pecam-1 , which leads to activation of a src family kinase ( src ) , which phosphorylates and activates vegfrs . higher vegfr3 ( green ) expression in lymphatic ecs increases their sensitivity to fss , resulting in a lower fss set point in lymphatic compared with blood ecs . ecs sense fss magnitude and compare it with a pre - existing value , the fss set point . deviations from this value activate remodeling mechanisms to alter vessel diameter and return fss to the steady - state level . we speculate that a more realistic mechanism for the fss set point requires several mechanosensitive elements , denoted a , b , and c , that have different sensitivities . pathway a is activated and reaches a maximum at low fss , while the other(s ) may require higher fss . the outputs from a , b , and c are denoted a , b , and c. these pathways would be organized into a network such that b is maximal at an intermediate fss level , the fss set point ( blue rectangle ) . the ratio of a and b determine the direction of remodeling , where high a/low c gives inward remodeling and high a/high c gives outward remodeling . this model is highly hypothetical and is meant only to illustrate the general class of theories that might explain the set point . tissue growth or metabolic activity increases nutrient and oxygen demand , which triggers peripheral arteriole relaxation and decreased resistance , increasing blood flow and hence fss in the upstream arteries ( michiels , 2004 ; segal , 2005 ; padilla et al . , 2011 ) . it has long been observed that changing flow magnitude and thus shear stress leads to proportional changes of vessel diameter to restore the initial shear stress level ( thoma , 1893 ; kamiya and togawa , 1980 ; kamiya et al . , 1984 ; langille , 1996 ; langille and odonnell , 1986 ; langille et al . , 1989 ; tronc et al . , 1996 ; tuttle et al . , 2001 ) . these observations suggested that ecs induce remodeling to maintain fss within a desired range , essentially a set point . sustained deviation outside this range then triggers readjustment of vessel diameter ( rodbard , 1975 ) . we recently obtained evidence that ecs have an in vitro fss set point at which flow activates pathways that promote blood vessel stabilization , whereas higher or lower fss triggers pathways characteristic of remodeling ( baeyens et al . , 2015 ) . we propose that fss at the set point promotes ec quiescence and vessel maturation , whereas fss outside that range triggers remodeling : inward for low and outward for high fss ( figure 1c ) . the specific signaling or gene expression pathways that distinguish low flow / inward versus high flow / outward remodeling have not been determined , though production of nitric oxide by endothelial nitric oxide synthase ( enos ) has been implicated ( rudic et al . , 2000 ; pecam1 is implicated in this process , since pecam1 mice are defective in both inward and outward flow - dependent remodeling ( chen and tzima , 2009 ; chen et al . , interestingly , pecam1 mice show constitutive activation of enos but loss of flow responses ( fleming et al . , 2005 ; mccormick et al . , 2011 corresponding to the large differences in flow magnitudes and patterns for different types of vessels ( lipowsky et al . 2006 ) , vascular and lymphatic ecs showed distinct set points in vitro that matched their fss levels in vivo ( baeyens et al . , 2015 ) . this difference was largely accounted for by levels of vegfr3 , which is highly expressed in lymphatic ecs compared with blood vascular cells ( kaipainen et al . , 1995 ) . it was shown that increasing vegfr3 levels increased cells sensitivity to fss , that is , the set point shifted to lower values . identification of vegfr3 as an element of the fss junctional mechanosensor ( coon et al . , 2015 ) thus appears to explain the distinct fss levels in veins versus lymphatic vessels ( figure 1b ) . classical control theory requires only a single measurement that is compared with a fixed value ( carpenter , 2004 ; figure 1b ) . however , signal transduction pathways in cells seldom operate that way . in the absence of digital measurements , a more likely mechanism is the existence of several molecular sensors with different sensitivities whose outputs are integrated to determine the response . to illustrate the concept , one possible mechanisms of integration is proposed in figure 1 , d and e. identification of these mechanosensors and characterization of their fss dose arterial and lymphatic flow patterns are highly pulsatile , whereas venous flow is nearly steady ( dixon et al . , 2006 ; huo and kassab , 2006 ) . these time - varying components can strongly influence endothelial responses . compared with steady flow with similar time - averaged magnitudes , pulsatile flow stimulates erk activity more strongly ( kadohama et al . , 2007 ) , while ampk activity is sensitive to pulse frequency ( zhang et al . , 2006 ) . comparison of proinflammatory oscillatory flow with anti - inflammatory pulsatile - flow patterns at atherosclerosis - prone versus atherosclerosis - resistant sites in the human carotid artery identified specific frequency components that exerted pro- or anti - inflammatory effects ( feaver et al . , 2013 ) . of clinical interest , left ventricle assist devices for heart failure patients generate nonpulsatile flow that induces arterial - venous malformations ( islam et al . , 2013 ) , suggesting that pulsatility is important for maintaining arterial identify . erk may mediate these effects , since it is strongly linked to arterial specification ( deng et al . , 2013 ) . these results imply that endothelial mechanosensors must decode subsecond - frequency characteristics , which necessitates rapid rates of both activation and inactivation . these kinetics , particularly the required inactivation rates , exclude even g protein signaling ; however , ion channels can have very rapid activation and inactivation kinetics . indeed , stretch - activated channels ( sacs ) have been implicated in fss - induced calcium entry ( mendoza et al . , 2010 ; mechanosensitive piezo channels have very rapid activation and inactivation rates ( coste et al . , 2010 ; gottlieb et al . , 2012 ) and are required for vascular development ( li et al . , 2014 ; ranade et al . , however , the nonselective sacs blocker gadolinium did not prevent ec alignment in response to fss ( malek and izumo , 1996 ) or other flow responses ( malek et al . , 1999 ; traub et al . , 1999 ) , potentially separating fss - induced polarity from mechanosensitive calcium influx . the correlation between atherosclerosis - prone regions of arteries and disturbed flow led to the idea that oscillatory shear , where flow reverses during part of the cardiac cycle , promotes plaque formation ( ku et al . interestingly , ecs in athero - prone regions fail to elongate and align in the direction of flow , and cells therefore experience flow at many angles , including perpendicular , whereas in athero - resistant regions of blood vessels , flow is parallel to the cell axis . in fact , recent studies suggest that plaque localization correlates more strongly with the perpendicular or transverse wall shear stress component than with oscillations ( peiffer et al . , 2013 ; mohamied et al . , 2015 ) interestingly , for elongated ecs in vitro , flow perpendicular to the cells axis promotes inflammatory responses , while flow parallel to the axis stimulates primarily anti - inflammatory pathways ( wang et al . , 2012 , 2013 ) . these effects correlate with the ability of steady laminar or unidirectional pulsatile fss to induce cell elongation and alignment in the flow direction in conjunction with suppression of inflammation , whereas low or oscillatory flow fails to induce alignment and promotes inflammatory pathways ( mohan et al . , 1997 ; chiu and chien , 2011 ; wang et al . , 2013 ) . the fortuitous observation that the proteoglycan syndecan 4 ( sdc4 ) is required for ec alignment in flow provided a way to test this idea . when sdc4 mice ( in which ecs fail to align ) were crossed into a high - cholesterol strain , atherosclerotic plaque not only increased but formed in normally resistant areas of laminar flow ( baeyens et al . , 2014 ) . yet in vitro , sdc4 was not required for other flow responses , and thus appears to be specifically required for sensing flow direction , which is separable from sensing flow magnitude . together , these results demonstrate that loss of alignment is causal for athero - susceptibility and that sdc4 is a component of the flow direction sensor . hemodynamic forces control vessel specification and maturation during development and continue to regulate vessel remodeling during postnatal and adult life . the exquisite ability of ecs to sense multiple aspects of fluid shear stress patterns allows them to coordinate the complex ballet of events involving different cell types and signaling pathways , to constantly adjust vessel structure and function . identifying molecular mechanosensors behind the distinct sensing of fss magnitude , direction , and pulsatility are major directions for future research . further , characterizing how downstream signaling pathways and gene regulation events are integrated in the context of growth and disease is required to better understand the amazing plasticity of our blood vessels . the finely tuned biomechanical responses discussed here govern health and disease in nearly every tissue from our first to our last heartbeat . understanding these processes is a major , exciting challenge for biomedical research in the coming years .
flowing blood exerts a frictional force , fluid shear stress ( fss ) , on the endothelial cells that line the blood and lymphatic vessels . 
 the magnitude , pulsatility , and directional characteristics of fss are constantly sensed by the endothelium . sustained increases or decreases in fss induce vessel remodeling to maintain proper perfusion of tissue . in this review , 
 we discuss these mechanisms and their relevance to physiology and disease , and propose a model for how information from different mechanosensors might be integrated to govern remodeling .