the changes in blood vessel diameter serve as an important physiological regulator of blood flow . these changes , caused by contraction and relaxation of vascular smooth muscle , can be regulated centrally and locally . the central regulation of cardiovascular function is achieved through neuronal control through complex projections from central and peripheral neurons [ 13 ] . the density of this neuronal innervation on the adventitial layer of blood vessels varies from tissue to tissue and among different vascular structures [ 46 ] . thus , local regulation of the blood vessel becomes important , especially in vessels with less abundant innervation or central regulation . it is required to achieve an immediate control of blood flow within a specific region in the tissue . autoregulation is an effective and efficient way to control the amount of blood flow locally without altering the neighboring systems significantly . in an isolated blood vessel , it has been shown that a sudden increase of transmural pressure reduces vessel diameter [ 810 ] , while a faster flow ( higher shear stress ) increases vessel diameter [ 9 , 1113 ] . all in all , the endothelial cells lining the lumen of the vessel have the ability to sense pressure and blood flow , and they are capable of transducing changes in mechanical forces into changes of vascular smooth muscle tone [ 14 , 15 ] . thus , endothelial cells are able to decrease and increase arterial diameter by altering contraction and relaxation behaviors of smooth muscle cells in the artery . biophysically , mechanical forces in the blood vessel can be observed in the forms of stretch due to distention of surrounding muscle , cyclic strain due to the pulsatile nature of blood flow , compression due to differential pressure along the vascular system , pressure due to surface force of the systolic blood flow , and shear stress due to drag force generated by the blood flow ( table 1 ) . these forms of mechanical forces may be physiologically impossible to differentiate in vivo because of the complex nature of the cardiovascular system . yet , these forces are known to be distinct from one another in cell culture or ex vivo studies [ 1720 ] . understanding the short - term and long - term effects of each individual force can therefore provide a better understanding of cardiovascular response , remodeling , adaptation , and disease . of the mechanical forces mentioned above , we will discuss biophysical shear stress , which is probably one of the most studied biophysical forces . primary cilia are usually classified as non - motile organelles with microtubules arranged in  9 + 0  fashion . it has been suggested that , like the nucleus , mitochondria , golgi , and other intracellular organelles , a primary cilium can also be viewed as a separate entity within a cell ( table 2 ) . a cilium can be studied as an organelle with five distinct domains : ( 1 ) the ciliary membrane , a specialized domain composed of a protein and with a lipid composition different from that of the rest of the plasma membrane ; ( 2 ) the soluble compartment , also known as the matrix compartment or cilioplasm ; ( 3 ) the axoneme , composed of nine pairs of microtubules with a highly structured transport motor cytoskeleton ; ( 4 ) ciliary tip , housed specialized proteins whose roles are still to be explored further ; ( 5 ) basal body , a mature  or  mother  centriole from which the primary cilium is projected . as micro - sensory compartments , cilia have functions that depend on mechano - proteins such as polycystin-1 and polycystin-2 ( figure 1 ) . thus , the overall functions of the sensory compartments depend on both functional and structural cilia proteins . within a blood vessel , an abrupt increase in blood pressure or shear stress can be detected by these sensory proteins localized in the cilia [ 16 , 24 ] . with cilium functioning as a local regulatory mechanism , the extracellular fluid mechanics can then be transduced and translated into a complex of intracellular signaling , which in turn would activate enos  an endothelial enzyme that synthesizes nitric oxide ( no ) gas . in particular , shear stress - induced calcium and no signaling has been reported in many endothelial cells . the released no will diffuse from endothelial cells to the neighboring smooth muscle cells , thereby promoting vasodilation [ 2628 ] . the overall effects of cilia function are thus to decrease total peripheral resistance , therefore lowering the blood pressure . the presence of primary cilia in vascular endothelia has been reported in human arteries [ 2931 ] and has been observed in cultured human cells [ 16 , 32 , 33 ] and adult vascular system in vivo [ 3438 ] . of particular interest is a high level of polycystin expression in endothelial cells , which is required for the structural integrity of blood vessels [ 3944 ] . the expression of polycystins in human endothelial cilia provides a critical link between cilia and the vasculature [ 16 , 32 , 33 ] . interestingly , the function of polycystin-1 as a mechanosensory molecule can be inactivated by proteolytic cleavage after exposure to high fluid - shear stress . this indicates that cilia function can also be regulated through modification of polycystin-1 via a high shear stress . this further suggests that in patients with high blood pressure , that is , high shear stress , cilia would very likely be unable to sense minute changes in blood pressure , which might result in failure to autoregulate the local circulatory system . this might increase the possibility of localized blood vessel injuries , such as aneurysm , atherosclerosis , dissection , edema , hemorrhage , and vascular ectasia , among others . throughout the cardiovascular system , patterns of fluid dynamics change considerably due to continuous vascular remodeling and patterning for microadaptation purposes [ 43 , 45 , 46 ] . these forces can initiate a complex of gene expressions [ 5 , 7 ] which may also alter cilia function or structure in endothelial cells . consistent with this idea , it has been shown that not all vasculatures have cilia [ 38 , 47 , 48 ] . only arteries with low fluid shear or high fluid turbulence have cilia , particularly longer , well - developed cilia . because prolonged exposure to high fluid - shear stress would induce cilia to disassemble , rather , endothelial cells may have other mechanisms , such as glycocalyx , to sense much higher mechanical forces [ 49 , 50 ] . to test the hypothesis that cilia are mechanosensitive organelles , endothelial cells without cilia were isolated and generated from tg737 mouse . to further confirm that polycystin-1 and -2 are sensory proteins in cilia , endothelial cells derived from mouse and human with polycystic kidney were used ciliary polycystin-1 and/or -2 are absent from the primary cilia in these cells . in tg737 functional assays were carried out by challenging these cells with various magnitudes of fluid - shear stress ( 0.550  dyne / cm ) . while shear - induced cytosolic calcium increase is observed in normal endothelial cells , neither endothelial cells ' isolated mutants nor diseased arteries exhibit this calcium response to shear stress [ 16 , 24 ] .   to validate cilia roles in fluid sensing , endothelial cells or arteries were subject to various mechanical stimulations ( table 1 ) . the specificity of cilia function is confirmed when the shear - insensitive cells or arteries could respond to other mechanical stimulation . most important is that pkd cells and arteries fail to produce nitric oxide ( no ) in response to fluid - shear stress . to understand how ciliary polycystins are required to activate a biochemical cascade for no production , various inhibitors were utilized to block the molecular functions . removing extracellular calcium with egta abolished both calcium and no production in normal endothelial cells . furthermore , l - name , an enos inhibitor , could block shear - induced no biosynthesis , but not cytosolic calcium increase . this indicates that extracellular calcium influx is an upstream and prerequisite event . to explore calcium - dependent mechanisms of no production , the roles of protein kinase c ( pkc ) and calmodulin were investigated with calphostin c and w7 , respectively . possible downstream effectors , including akt , pkb , and pi3k , were examined with pharmacological blockers akt inhibitor ii , ly-294,002 , and wortmannin . interestingly , only akt / pkb , but not pi3k , is involved in shear - induced no production ( figure 2 ) . polycystic kidney disease ( pkd ) is characterized by bilateral enlarged cystic kidneys , which have been associated with primary cilia dysfunction [ 22 , 51 , 52 ] . these abnormalities may include hypertension , cerebral and coronary artery aneurysms , mitral valve prolapse , aortic root dilation , dissection of the thoracic aorta , aneurysm formation in the abdominal aorta , vascular ectasia , and abnormal function of the microvascular bed [ 5356 ] . these include hypertension ( 78% ) , cardiac valve disorders ( 25% ) , and intracranial aneurysms ( 10% ) . hypertension , in particular , has been a continual risk factor for other cardiovascular complications in pkd . similar to cystogenesis , pathogenesis of hypertension in pkd has also been associated with primary cilia dysfunction . within the context of clinical hypertension , there are two theories that could help describe the pathogenesis of hypertension in pkd ( table 3 ) . the first theory points to inherent cardiovascular dysfunctions as the primary cause of hypertension ; the second theory brings about the cystic kidney itself as the origin for hypertension . in an observational study of 312 children with pkd pkd children with high blood pressure have faster renal growth than those with lower blood pressure . consistent with this view , it has been suggested that high blood pressure can actually promote faster cyst growth [ 59 , 60 ] . of note is that hypertension occurs at a much earlier age in patients with pkd than in the general population . the median age for hypertension in pkd patients is about 30 years , compared with a median age of 4555 years in patients with essential hypertension . hypertension occurs in children even before they are diagnosed with pkd [ 6366 ] or before any substantial reduction in glomerular filtration rate is observed [ 67 , 68 ] . to examine endothelial function in pkd , the plasma concentrations of vasodilator nitric oxide were measured in pkd patients and healthy controls . in this study , the plasma concentration of nitric oxide was reduced in pkd patients , confirming an association between pkd and endothelial dysfunction . the endothelial dysfunction in pkd may thus be associated with abnormal cilia role in sensing fluid - shear stress and other downstream signaling mechanisms ( figure 2 ) . to further substantiate the endothelial dysfunction in pkd , levels of adma ( a marker of an inhibitor of nitric oxide synthase ) were significantly increased in patients with early pkd compared to healthy age - matched individuals . although the significance of adma in pkd is not immediately understood , endothelia - dependent vasodilation offers substantial evidence which is too important to ignore . although ciliary therapy does not exist today , it is appealing and tempting to speculate the possibility of treatment for localized blood vessel injuries such as aneurysm , atherosclerosis , dissection , edema , hemorrhage , and vascular ectasia , among others in pkd . in particular , endothelium - dependent relaxation is impaired , and endothelial nitric oxide synthase activity is decreased in patients with pkd [ 7173 ] . the endothelial dysfunction due to impaired release of no in pkd patients becomes a crucial pathogenesis of hypertension . the imbalance in endothelium - derived vasoactive mediators might therefore need to be considered seriously in pkd patients [ 74 , 75 ] . it is believed that as renal cysts progress , the cysts will cause structural damage in the nephrons , which leads to distortion of the renal architecture ( figure 3 ) . such a distortion would compress the renal vasculature and attenuate the renal vessels , causing intrarenal ischemia and activation of the renin - angiotensin - aldosterone system ( raas ) . not surprisingly , several studies have shown that the ace - i ( angiotensin - converting enzyme inhibitor ) or the arb ( angiotensin receptor blocker ) is effective in lowering blood pressure in pkd [ 79 , 80 ] . activation of the raas , which is well documented in the clinical course of the disease   and in pkd mouse models [ 82 , 83 ] , has been proposed to contribute to hypertension seen in pkd patients . raas activation has also been found in normotensive and hypertensive pkd patients , regardless of their blood pressure and renal function . it is believed that the high level of circulating angiotensin ii in pkd patients also contributes to the development of vascular hypertrophy , which is further implicated in vascular remodeling . changes in the vasculatures during the course of the pkd progression have therefore been observed in both human [ 8690 ] and animal [ 9195 ] studies . it was also reported that the sympathetic nerve activity is increased in hypertensive patients with pkd , regardless of renal function [ 96 , 97 ] . however , it is not immediately understood whether the sensitivity to sympathetic nerve activity is a secondary effect due to an increase in raas system . in a 3-year prospective randomized double - blind study , ace - i ramipril and the beta - blocker metoprolol were both effective for use as a first - line therapy in hypertensive pkd patients . however , it was suggested that aggressive blood pressure control with these agents is necessary in order for them to be beneficial for pkd patients . of apparent complexity is that angiotensin can stimulate the sympathetic nervous system and that sympathetic nerve activity can also stimulate raas [ 100 , 101 ] . at least in murine models of pkd , bilateral renal denervation could reduce cystic kidney size , cyst volume and most importantly , systolic blood pressure . it is therefore very likely that sympathetic nerve activity would activate raas system , which would increase blood pressure .   since cardiovascular abnormalities are thought to initiate from the cystic kidneys in pkd , there has been a great interest in studying the outcomes after renal transplantation in these individuals . interestingly , renal transplant recipients with pkd still showed an increase in cardiovascular morbidity as seen in non - pkd transplant recipients . in a different report of eleven transplant cases in hypertensive pkd , only six patients showed improved blood pressure after transplantation . improved blood pressure was defined as the ability to reduce antihypertensive drug treatment after renal transplantation . these results suggest that while renal transplantation seems to have some beneficial outcomes , it is not sufficient to eradicate the hypertension in pkd patients . primary cilium dysfunction has been associated with pkd , and primary cilia have also been proposed to regulate blood pressure . we believe that because our knowledge on cilia biology is still relatively limited compared to other organelles within a cell , there are certainly many more questions than answers that we could provide at present . in order to better understand the relationship between cilia and pathogenesis of hypertension , we need to understand the physiological roles of cilia in more detail and in many other organ systems . for example , vascular endothelial cilia have recently been proposed to regulate cell division   and endothelial - to - mesenchymal transition . in addition , the presence of cilia in vascular smooth muscle cells has also been reported , and sensory polycystin-1 and polycystin-2 complex is localized in these cilia [ 107 , 108 ] . although their roles are not clear at present , the vascular cilia are positioned in such a way that they maintain a specific alignment with respect to the lumen of the artery . further studies of the role of this alignment may be necessary to shed light on their possible functions with regard to vascular hypertension . whether or not dysfunction in primary cilia causes hypertension in pkd , there is certainly much work remaining . we are on the verge of applying our concept and understanding of pkd to better clinical practice and patient outcomes . nonetheless , early and effective treatments of hypertension are clinically very important to decrease the morbidity and mortality of patients with pkd .
local regulation of vascular tone plays an important role in cardiovascular control of blood pressure . aside from chemical or hormonal regulations , this local homeostasis is highly regulated by fluid - shear stress . 
 it was previously unclear how vascular endothelial cells were able to sense fluid - shear stress . 
 the cellular functions of mechanosensory cilia within vascular system have emerged recently . in particular , hypertension is insidious and remains a continuous problem that evolves during the course of polycystic kidney disease ( pkd ) . 
 the basic and clinical perspectives on primary cilia are discussed with regard to the pathogenesis of hypertension in pkd .