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the growing prevalence of diabetic retinopathy ( dr ) , the common ocular complication of diabetes mellitus , is a critical problem for global public health [ 1 , 2 ] .  
early nonproliferative stages of dr are characterized by blot hemorrhages and vascular abnormality such as retinal vascular microaneurysms or hyperpermeability which could cause diabetic macular edema ( dme ) .  
proliferative diabetic retinopathy ( pdr ) , later stage of the diseased state , causes neovascularization , vitreous hemorrhages , preretinal fibro - vascular proliferation , and tractional retinal detachment .   while visual acuity is not always affected in early stages , progression of the disease leads to severe vision loss .
panretinal photocoagulation ( prp ) and vitreoretinal surgery remain the primary therapeutic strategies for progressed dr .   however , prp is destructive to the retina and accompanied by adverse effects such as decreased visual acuity , increased risk of macular edema , and pain [ 3 , 4 ] .  
moreover , recent advances in vitreous surgery can not always achieve a satisfying visual acuity .  
now it is at a point where new alternative and adjunctive agents from the earlier stages are urgently required because of overwhelming patient 's physical and economic burdens of these treatments .
the various clinical findings in earlier dr stages are related to endothelial damage secondary to increased leukocyte adhesion mediated through adhesion molecules , intercellular adhesion molecule-1 ( icam-1 ) , and leukocyte 2-integrins ( cd18/cd11a and cd18/cd11b ) [ 68 ] .  
in addition , the critical mechanism of this leukocyte - induced endothelial damage is the interaction of endothelial fas with fas ligand , expressed on adherent leukocytes in diabetic rats   and dr patients .
recent accumulating evidences indicate that vascular endothelial growth factor ( vegf ) plays a critical role in pathogenesis of both dme and neovascularization in pdr [ 11 , 12 ] .  
clinical studies with anti - vegf antibodies are potentially useful strategy and improve outcome for treating dr .  
however , the adaptation is only for progressed states and there is a possibility of systemic adverse complications such as hypertension , cerebrovascular accidents , and myocardial infarcts by anti - vegf therapy .   
meanwhile , neovascularization and proliferative vitreoretinopathy ( pvr ) are hallmark of the later dr stages .  
erk1/2 signaling promotes the proliferative activities of endothelial cells in angiogenic processes [ 15 , 16 ] .  
moreover , endothelial migration is mediated by rho - kinase ( rock ) pathway which activates remodeling of endothelial f - actin cytoskeleton .  
our recent findings indicated that hyalocytes , a known resident macrophage in the cortical vitreous under physiological conditions , appeared to be involved in the pathogenesis of pvr associated with a cicatricial contraction of proliferative membranes in pdr [ 1820 ] .   the expression of -smooth muscle actin ( -sma ) and phosphorylation of myosin light chain ( mlc ) in hyalocytes , which is associated with stress - fiber formation and contractile rings , are facilitating cell contraction [ 21 , 22 ] .  
we demonstrated that vitreous from patients with pdr significantly promoted expression of -sma and phosphorylation of mlc , and enhanced contraction of hyalocyte - containing collagen gels , compared with vitreous from patients with nondiabetic controls .             in this paper
, we first place the rho / rock pathway plays a critical role in diabetic retinal microvasculopathy , neovascularization , and tractional retinal detachment associated with a cicatricial contraction of proliferative membranes .  
we then describe our current knowledge about rock inhibition as a new strategy in the total management of dr from its early to late stages .
recent studies have revealed that small gtp - binding protein rho and its target protein rock are implicated in the important physiological roles such as cell adhesion and migration mediated through mlc phosphorylation [ 19 , 24 ] .  
rho activity is also increased in bovine aortic endothelial cells treated with high glucose , and involved in the pathogenesis of renal and aortic complications during diabetic states [ 26 , 27 ] .  
furthermore , we revealed that rho / rock pathway is activated in retinal microvessels during diabetes ( figures 1(a)1(e ) ) .   
rho / rock pathway promotes leukocyte adhesion to the microvasculature by affecting the expression and function of adhesion molecules , including icam-1 [ 28 , 29 ] and integrins .   moreover , rock causes firm adhesion through the activation of ezrin , radixin , and moesin in endothelial cells , which jointly form the anchoring structures for leukocytes ' integrins [ 31 , 32 ] .   
these findings suggest that elevated activity of the rho / rock pathway is involved in the pathogenesis of diabetic microvasculopathy mediated through leukocyte adhesion .
rho / rock signaling is also involved in the pathogenesis of vegf - induced angiogenesis .   in endothelial cells
rock pathway plays a critical role in vegf - induced endothelial migration by regulating stress fiber formation associated with mlc phosphorylation [ 17 , 33 ] .  
moreover , recent in vivo studies have also demonstrated that the rock pathway plays a critical role in angiogenesis [ 34 , 35 ] .
previously we showed tgf-2 contributes to transdifferentiation of hyalocytes into -sma positive myofibroblast - like cells that causes hyalocyte - containing collagen gel contraction .  
moreover , we revealed that tgf-2 , overexpressed in the vitreous and contractile membranes of pdr patients , activates rock pathway and forms stress fibers and contractions mediated through rock activation [ 20 , 23 ] .  
these results suggest the central role of rock in the cicatricial contraction of proliferative membrane in pdr patients .
fasudil , a potent and selective rock inhibitor , is relatively safe and effective in the treatment of cardiovascular disease including cerebral and coronary vasospasm , angina , hypertension , and heart failure with no serious adverse side effect in fasudil - treated patients .   in our animal experiments ,
intravitreal injection of fasudil did not cause apparent electrophysiological or morphological changes in retinal tissues at least within its effective concentrations .
however , several adverse effects such as hepatic function abnormal , intracranial hemorrhage , and hypotension have been reported [ 37 , 38 ] .
we thus need further examination regarding the safety and adverse effects of rock inhibitor before its clinical use in the field of intraocular diseases .              
nevertheless , we recently could reveal the therapeutic potential of fasudil in the management of earlier stages of dr .  
treatment with intravitreal injection of fasudil significantly decreased retinal leukocyte adhesion in diabetic rat mediated through reduction of rock activation .  
moreover , fasudil effectively suppressed endothelial damage , even when leukocytes firmly adhered to the endothelium ( figures 1(f)1(i ) ) .  
this suggests that fasudil directly causes endothelial protection in addition to its impact on leukocyte adhesion .
rho / rock inactivates endothelial nitric oxide synthase ( enos ) in human umbilical venous cells .  
enos generates physiological levels of nitric oxide ( no ) , a potent vasodilator   and antiapoptotic factor [ 41 , 42 ] .  
in addition , the protective effect of fasudil on microvascular endothelial cells was significantly blocked by nos inhibition with l - name , without apparent effect on leukocyte adhesion in vitro .  
these findings suggest that fasudil has a direct endothelial protective potential through induction of physiological levels of no , synthesized by enos .
we demonstrated that rock inhibitor could inhibit vegf - elicited bovine retinal capillary endothelial cell ( brec ) migration and proliferation in vitro and corneal neovascularization in vivo .  
a rock inhibitor fasudil had inhibitory effect on brec migration with a scratch - wound assay .  
moreover , fasudil could inhibit vegf - induced brecs [ h]-thymidine incorporation and erk1/2 phosphorylation , whose activity indicates the proliferative activities of endothelial cells in angiogenic processes .   in vivo , fasudil strongly attenuated vegf - induced corneal neovascularization in a corneal pocket assay .
we could also demonstrate the therapeutic potential of rock inhibitor fasudil in the management of later stages of dr .   in hyalocyte - containing collagen gels assay , fasudil almost completely abolished the pdr vitreous - induced collagen gel contraction mediated through the suppression of mlc phosphorylation ( figures 2(a ) and 2(b ) ) .   in experimental pvr rabbit model ,
fasudil also effectively disrupted -sma organization and blocked contraction of proliferative membrane ( figures 2(c)2(i ) ) .   
statins , inhibitors of the 3-hydroxy-3-methyl - glutaryl- ( hmg- ) coa reductase , are widely used to reduce endogenous cholesterol synthesis and improve hypercholesterolemia .   by inhibiting hmg - coa reductase
we demonstrated that simvastatin almost completely inhibited vitreous - induced contraction of the collagen gels in exvivo and proliferative membrane in experimental pvr model mediated through rock inhibition .  
rho / rock activation plays an important role in the pathogenesis of vasoconstriction , such as cerebral and coronary spasm   or hypertension , by no - dependent mechanisms .  
we could show that intravitreal injection of lysophosphatidic acid , a potential rho activator , induced severe retinal vessel constriction ( figures 3(a)3(c ) ) .  
recent studies suggested that rock inhibitor fasudil improved hemodynamic states in human , and also dilated rat retinal vessels , and increases blood flow .  
these results suggest that fasudil has preventable benefit on retinal ischemia during diabetes through improvement of hemodynamics in the retinal vessels .
retinal ischemia secondary to dr causes functional and irreversible damage not only in retina vasculature but also in retinal neuronal cells .  
chronic loss of neuronal cells from the inner retina by increasing the frequency of apoptosis reduces the thickness of the nerve fiber layer in diabetic retina .  
impaired retinal electrophysiology and neurodegeneration have been shown in diabetic patients [ 51 , 52 ] .  
recent studies revealed that rho / rock pathway also seems to be associated with the pathogenesis of this neuronal damage .  
abnormal activation of the rho / rock pathway is important in the pathogenesis of several neurological diseases .   in rat retina , rho / rock pathway
is also involved in n - methyl - d - aspartat - induced neurotoxicity in the rat retina . .
these studies suggest that rock inhibitor would protect against neuronal damage by acting directly on neurons .  
in fact , the rock inhibitor y-27632 increases regeneration of retinal ganglion cell in the rat optic nerve crush model .   moreover , rock inhibition attenuates ischemia - induced retinal neuronal cell death by inhibiting leukocytes extravasation and release of proinflammatory cytokines such as tnf- or il-6 in vitro / vivo [ 56 , 57 ] .  
these data suggest that inhibition of rho / rock pathway leads to neuroprotective effect and promote retinal cell survival during diabetes .
rho / rock pathway is involved throughout the pathogenesis of dr , particularly in diabetic retinal microvasculopathy , neovascularization , and tractional retinal detachment associated with cicatricial contraction of preretinal proliferative membranes ( figure 4 ) .  
since we must consider frequent intravitreal injections as administration method due to a short biological half - life time of the compound in the vitreous cavity , we are considering intravitreal implantation of a slowly releasing drug - delivery system
.   for preventable benefit on progressing retinal microvascular damage and keeping good visual acuity , timing of intravitreal fasudil implantation prefers when early clinical dr findings such as microaneurysm begin to appear .  
in addition , pre- and postoperative intravitreal implantations for active pdr patients with proliferative membrane are also considered to be effective for prevention of pvr and tractional retinal detachment .  
whereas further basic and clinical studies to reveal the effectiveness and safety of rock inhibitor are needed for clinical use in the field of eye diseases , rock inhibition might become a novel therapeutic strategy in the total management of dr from its early to late stages .
the increasing global prevalence of diabetes is a critical problem for public health .   
 in particular , diabetic retinopathy , a prevalent ocular complication of diabetes mellitus , causes severe vision loss in working population .   
 a better understanding of the pathogenesis and the development of new pharmacologic treatments are needed .   
 this paper describes the relevance between rho / rock pathway and the pathogenesis of diabetic retinopathy from its early to late stages .   
 moreover , the therapeutic potential of rock inhibitor in the total management of diabetic retinopathy is discussed .