fibrogenic progression of chronic liver diseases ( clds ) , eventually leading to the development of liver cirrhosis and related complications including hepatocellular carcinoma ( hcc ) , is intimately associated with pathologic angiogenesis and sinusoidal remodeling.1 , 2 , 3 , 4 , 5 , 6 this is not surprising because angiogenesis is a major feature of any wound healing response and chronic activation of wound healing is a general mechanism involved in the progression of clds.7 , 8 , 9 , 10 some researchers , including the authors of this review , go further2 , 3 , 4 , 9 , 10 , 11 , 12 , 13 , 14 , 15 in suggesting additionally that 1 ) hypoxia ( the most obvious stimulus for angiogenesis , commonly detected in progressive clds1 , 2 , 3 , 4 , 5 , 6 , 16 ) , hypoxia - inducible factors ( hifs ) , and angiogenesis may have a major role in sustaining and potentially driving liver fibrogenesis ; 2 ) hepatic myofibroblasts ( mfs ) , regardless of origin , are critical cells in governing and modulating the interactions between inflammation , angiogenesis , and fibrogenesis ; 3 ) liver angiogenesis has a role in the genesis of portal hypertension and related complications in advanced stages of clds ; and 4 ) microparticles / microvesicles released by either fat - laden hepatocytes or portal mfs have an emerging role in mediating angiogenesis and vascular remodeling . this review offers a synthesis of the most relevant recent data and opinions regarding the close relationship between liver angiogenesis and fibrogenesis . established concepts about mechanisms of liver angiogenesis , liver fibrogenesis , and cld progression will not be addressed . moreover , in this review , the relationship between angiogenesis and portal hypertension and related complications are not discussed ; readers interested in this specific topic should refer to a recent authoritative review . liver angiogenesis occurs in both physiologic ( ie , liver regeneration ) and pathologic conditions , including ischemia , progressive clds , hepatocellular carcinoma , and metastatic liver cancer.1 , 2 , 3 , 4 , 5 angiogenesis in the liver is similar to angiogenesis in other tissues and organs ; however , as suggested by several groups,1 , 2 , 3 , 4 , 5 , 10 , 11 , 12 pathologic angiogenesis occurring during the progression of clds can be significantly affected by liver - specific events , interactions between different hepatic cell populations , and the involvement of atypical proangiogenic mediators . from a general point of view , the pattern of fibrosis that predominates in a specific cld is relevant to angiogenesis . although pathologic liver angiogenesis has been described in all clds irrespective of etiology , it is much more prominent under conditions of bridging or postnecrotic fibrosis ( eg , in chronic viral infection or , to a lesser extent , in autoimmune diseases ) than in conditions characterized by pericellular or perisinusoidal fibrosis ( as in non - alcoholic fatty liver disease or alcoholic liver disease ) or by biliary fibrosis.3 , 9 , 10 this suggests an inverse correlation between angiogenesis and the potential for fibrosis reversibility , which is more evident in conditions characterized by pericellular or perisinusoidal fibrosis and biliary fibrosis than in those associated with bridging fibrosis . this may be related to the unique tissue localization , phenotypic profile , and functional role of hepatic stellate cells ( hscs ) . hscs , which in physiologic conditions synthesize extracellular matrix components in the space of disse , store retinoids and possibly contract in response to vasoactive mediators to modulate sinusoidal blood flux , are also liver - specific pericytes . during the progression of clds , hscs are the most relevant myofibroblast precursors and profibrogenic hepatic cells.2 , 17 , 18 , 19 , 20 , 21 hscs , particularly in their activated and mf - like phenotype ( hsc / mfs ) , modulate angiogenesis in a way that , as we will describe , relates to the role attributed to them as microcapillary pericytes . hepatic mfs , a heterogenous population of profibrogenic , highly proliferative , and contractile cells , can also originate from portal mfs and bone marrow - derived stem cells recruited into the injured liver , and these may also play a role in angiogenesis.17 , 18 , 19 , 20 , 21 , 22 the relevance of intense cross - talk between hepatic cell populations in pathologic angiogenesis is strongly supported by the knowledge that major proangiogenic mediators such as vascular endothelial growth factor ( vegf ) and platelet - derived growth factor ( pdgf ) , are produced and released by several liver cell types involved in cld progression , including hypoxic hepatocytes and hypoxia - responsive macrophages and mfs.1 , 2 , 3 , 9 , 10 , 11 , 12 the role of liver - specific proangiogenic mediators such as angiopoietin - like-3 peptide ( angptl3 ) is controversial . angptl3 , which belongs to a family of mediators described as playing major roles in the trafficking and metabolism of lipids , was reported to induce haptotactic endothelial cell adhesion and migration , possibly by binding to v3 integrin . however , no further studies have been published on the role of this mediator in either physiologic or pathologic liver angiogenesis . as we will discuss , a more interesting role is attributed to the antiangiogenic protein vasohibin , which may have a dual role in inhibiting not only angiogenesis but also fibrogenesis , likely by deactivating hscs . angiogenesis is best defined as a dynamic , hypoxia - stimulated , and growth factor - dependent process leading to the formation of new blood vessels from preexisting ones.25 , 26 hypoxia and hifs are critical in sustaining the fibrogenic progression of clds , representing a persistent driving force able to directly affect the behavior of hepatic cell populations , including profibrogenic and proangiogenic mfs.1 , 2 , 3 , 4 , 5 , 10 , 11 , 12 , 13 , 16 detection of hypoxic areas is a common finding at any stage of cld , increasing progressively from early injury to the development of cirrhosis , with hypoxia and hifs serving throughout as proangiogenic stimuli in the overall , etiology - independent scenario of chronic wound healing . cld progression itself is a major contributor to hypoxia due to the formation of regenerative nodules of parenchyma surrounded by evolving fibrotic septa and vascular remodeling that , along with progressive capillarization of the sinusoids , leads to an impairment of oxygen diffusion . a vicious circle between fibrosis and pathologic angiogenesis is likely to occur10 , 12 , 27 in which parenchymal hypoxia , through the action of hifs , up - regulates expression of wound healing - related factors and mediators that should facilitate liver repair and revascularization . however , pathologic angiogenesis can be inefficient due to the immaturity and permeability of vegf - induced neovessels and , as a result , may be unable to correct liver hypoxia . pathologic angiogenesis and hypoxia may act synergistically in disrupting normal tissue repair , thereby promoting the development of liver fibrosis . the connection between pathologic angiogenesis and fibrogenesis in progressive clds is strongly suggested by their parallel development in all major human forms of cld and animal models of clds , with several laboratories describing high numbers of endothelial cells and microvascular structures within fibrotic septae and in expanded portal areas.1 , 2 , 3 , 4 , 5 , 10 , 11 , 12 , 13 , 16 , 28 , 29 , 30 the response to hypoxia and vegf ( the major proangiogenic target gene ) expression can be seen in liver sinusoidal endothelial cells ( lsecs ) and in hepatocytes1 , 3 , 4 , 10 , 28 and hsc / mfs of developing septa and at the borders of more mature and larger fibrotic septa.29 , 30 studies performed in hif-1 liver conditional knockout mice provided the first definitive in  vivo evidence for hypoxia - dependent induction of fibrogenesis . however , the most convincing evidence relating angiogenesis and fibrogenesis came through in  vivo studies indicating that experimental antiangiogenic therapy was highly effective in significantly reducing fibrogenic progression . as summarized in table  1 , whatever the specific molecule or tool employed , experimental antiangiogenic therapy always resulted in a significant reduction not only of angiogenesis but also of the inflammatory infiltrate , the number of -smooth muscle actin ( -sma)-positive mfs and the extent  of fibrosis.32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 in some studies , experimental antiangiogenic therapy also resulted in a significant reduction of portal pressure and collateral vessel formation , as reported with sorafenib in cirrhotic animals34 , 43 and with different molecules and tools in portal hypertensive animals.9 , 24 , 44 , 45 , 46 , 47 , 48 , 49 to our knowledge , only two studies have been published that represent exceptions to this general finding . the first one was published in 2009 by patsenker et  al , who reported that pharmacologic inhibition of integrin 3 by cilengitide , although able to suppress liver angiogenesis , significantly worsened experimental liver fibrosis . a second experimental and clinical study suggested that the development of liver fibrosis was associated with decreased expression of vegf and sinusoidal rarefication of the fibrotic scar . these investigators reported that experimental resolution of fibrosis was accompanied by an increase in hepatic vegf levels and revascularization of fibrotic septa , events that were prevented by ablating vegf in myeloid cells or through pharmacologic inhibition of vascular endothelial growth factor receptor type 2 ( vegf - r2 ) signaling . the question of whether available antiangiogenic drugs might be useful in treating patients with cirrhosis and portal hypertension remains unanswered , with some positive data reported in cirrhotic patients with hcc ; however , several significant concerns were raised related to the known severe side effects of these drugs ( eg , sorafenib ) as well as  the increased risk of bleeding reported in cirrhotic patients with hcc . on the other hand , although vegf is unequivocally a critical profibrogenic mediator and has a well - established role in endothelial cell survival and proliferation , it may have also a role in fibrosis resolution . while blocking the interaction between vegf and vegf - r2 does not result ( as hypothesized ) in an improvement or acceleration of fibrosis resolution , the availability of vegf is critical in chemokine ( c - x - c motif ) ligand 9 ( cxcl9)- and matrix metalloprotease 13 ( mmp13)-dependent fibrosis resolution in different murine models of fibrosis . this apparent paradox is explained by the fact that blocking vegf - r2 effectively blocks vegf - dependent recruitment of mononuclear cells and changes in vascular permeability . blocking vegf - r2 thereby potentially reduces the recruitment of  resolution  macrophages , which have an important role in fibrosis reversal . indeed , in that study , the degree of impairment of fibrosis resolution obtained by blocking vegf - r2 was nearly identical to that seen with macrophage depletion . chronic liver inflammation is a key requirement for the progression of liver fibrosis , but there is little known about its role in promoting fibrosis - associated angiogenesis . although inflammation - associated angiogenesis may contribute to both initiation of clds and their progression toward cirrhosis and hcc , the available data refer primarily to hcc and to macrophages in the tumor microenvironment.56 , 57 , 58 , 59 studies performed using specimens from cld patients and from mouse models have shown that chemokine - dependent accumulation of monocyte - derived macrophages represents a relevant mechanism for perpetuating hepatic inflammation and promoting fibrogenesis . in particular , the chemokine receptor 2 ( ccr2 ) and its ligand ccl2 have a key role in promoting the accumulation of certain monocyte subsets in the liver , in particular ly6c ( gr1 ) monocytes . macrophages derived from these monocytes release proinflammatory cytokines and can directly activate profibrogenic hepatic mfs . accordingly , ccl2-dependent infiltrating macrophages are critical in sustaining angiogenesis in experimental models of clds . a study has shown that these cells promote angiogenic vessel sprouting , particularly in the portal vein system , by releasing vegf - a and other potential proangiogenic factors such as matrix metalloprotease 9 ( mmp9 ) . this study convincingly demonstrated that angiogenesis is induced even at the initial stages of liver fibrosis and that hepatic neovascularization correlates with fibrosis stage . infiltrating and ccl2-dependent inflammatory cells mediate induction of fibrosis - associated pathologic angiogenesis , and , accordingly , pharmacologic inhibition of ccl2 blocks angiogenesis in experimental fibrosis by inhibiting the infiltration of ccl2-dependent monocyte / macrophages . hepatic mfs , particularly hsc / mfs , play a critical role in cld progression through their unique ability to act as hypoxia - sensitive and cytokine- and chemokine - modulated cellular mediators at the crossroads between chronic liver injury , inflammation , pathologic angiogenesis , and fibrogenesis.1 , 2 , 3 , 4 , 5 , 10 mfs are critical target cells , able to integrate signals from the microenvironment ( including from hypoxia , contact with altered extracellular matrix , and plasma proteins ) and from surrounding liver cells , acting as both profibrogenic and proangiogenic effector cells ( see figure  1 ) . we propose that the overall proangiogenic role of mfs is the result of their interactions with surrounding hepatic cells and their exposure to the altered hepatic microenvironment during cld progression . in the next sections , we focus particularly on lsecs and the relevance of the interactions between lsecs , hsc , and hsc / mfs , as  well as on both hypoxia - dependent and hypoxia - independent responses of activated mfs . under physiologic conditions , the intrahepatic vascular system is composed of different kinds of vessels , including liver sinusoids , portal venules , hepatic arterioles , central venules , and lymphatic vessels . these vessels are composed of endothelial cells and smooth muscle cells as well as , for liver sinusoids , hscs , which act as liver specific pericytes . all these cells , plus resident kupffer cells and other blood - derived cells , interact with each other . signaling between these cells maintains sinusoidal homeostasis and lsecs represent the majority of liver endothelial cells and have a morphologic and functional phenotype that is strikingly different from that of endothelial cells of other vascular units in the liver and elsewhere . fenestration and a lack of a typical basement membrane are predominant features of the lsec phenotype but are lost in clds.62 , 63 under physiologic conditions , quiescent hscs , which reside in the space of disse and interact through their multiple processes with hepatocytes and lsecs , contribute  to vitamin a and retinoid metabolism as well as to deposition and remodeling of the extracellular matrix in the space of disse . quiescent hscs , which also interact with  the axonal processes of autonomic nerve fibers , are liver - specific pericytes , able to respond to a variety of vasoactive mediators and may regulate sinusoidal blood flow through their perisinusoidal processes.62 , 63 , 64 , 65 , 66 the literature suggests that human hscs contract mainly in response to endothelin-1 ( et-1 ) , thrombin , and angiotensin - ii , and relax in response to nitric oxide ( no ) and no donors , prostaglandin e2 , somatostatin , and adrenomedullin.64 , 65 there is considerable support for the paradigm that under conditions of chronic liver injury two features predominate : 1 ) overproduction of et-1 by activated hscs ; and 2 ) a significant reduction in no release by lsecs.62 , 63 , 64 , 65 hscs , which are a major source of et-1 , also represent a target for this vasoactive molecule during liver injury , with et-1 ( either from lsecs or activated hscs , acting in a paracrine or autocrine way ) exerting a prominent contractile effect on hscs and mfs , and likely contributing to portal hypertension in the cirrhotic liver67 , 68 , 69 as well as having a growth inhibitory effect on hsc / mfs . during cld progression , this results in an imbalance in vasoactive mediators and leads to abnormal sinusoids , with remodeling and constriction of the intrahepatic sinusoidal vasculature and a resulting increase in hepatic vascular resistance early in intrahepatic portal hypertension . as highlighted by iwakiri et  al , this differs from events in the mesenteric vascular bed , which are characterized by vasodilation and reduced resistance from up - regulation of vasodilators such as no ; this in turn leads to increased flow to the portal vein . the combined result of changes in the intrahepatic and mesenteric vasculature is an increase in intrahepatic resistance and portal blood flow from the splanchnic circulation , leading to increased portal pressure and portal hypertension . regulation of the phenotype of lsecs can be viewed as the net result of the action of different signals that include soluble factors ( mainly vegf , angiopoietins , ephrins , and fibroblast growth factors ) and mechanical forces such as those due to shear stress . these signals are critical in modulating endothelial no synthase ( enos ) activity in lsecs , resulting in the regulation of flow and vascular tone in the liver sinusoids.62 , 71 lsecs release in a paracrine way several mediators that are involved in maintaining a  physiological  lsec phenotype but also affect the early response of hscs . for example , lsecs can produce the cellular isoform of fibronectin in response to injury ; fibronectin has been reported to stimulate hsc synthesis of et-1 . et-1 , in turn , may differentially affect proliferation of hscs , promoting proliferation in transiently activated hscs but inhibiting it in fully activated hscs.70 , 73 during cld progression , lsec phenotype changes dramatically during the so - called capillarization of sinusoids in association with a reduction in enos activity and no synthesis . this is possibly due to extensive posttranslational dysregulation of enos as a consequence of changes in phosphorylation or interactions with proteins such as calmodulin , caveolin-1 , and protein kinase b ( akt).74 , 75 the reduction in no release by lsecs is believed to have a more direct role in sustaining fibrogenesis because no contributes to the maintenance of quiescence of hscs and may induce apoptosis or reversal of phenotype of activated hscs , with reduced levels of no facilitating hsc activation.76 , 77 the scenario may be even more complex because hscs can produce no after injury , possibly in response to up - regulation of inducible nos activity induced by proinflammatory cytokines or endotoxemia . lsecs , through interactions between vegf and vegf - r2 , can release wnt2 and hepatocyte growth factor , which sustain proliferation of hepatocytes ; moreover , a significant amount of hepatocyte growth factor is also released by bone marrow - derived lsec progenitor cells . lsecs from the livers of mice with biliary fibrosis have been reported to release profibrogenic mediators such as transforming growth factor  , bone morphogenetic protein 2 , and pdgf - c and to decrease the release of putative antifibrotic factors such as follistatin and apelin . increased expression of vegf in specimens from fibrotic or cirrhotic patients colocalizes with areas of hypoxia and is mostly limited to hepatocytes and mfs.28 , 29 , 30 mfs respond to hypoxic conditions through hif-1-dependent up - regulation of vegf and angiopoietin-1 ( ang-1 ) and of their respective receptors vegf - r2 and tie2.29 , 80 , 81 , 82 , 83 , 84 , 85 exposure of hsc / mf to hypoxic conditions also results in hif-1-dependent up - regulation of ccr1 , ccr5 , macrophage migration inhibitory factor , interleukin-13 receptor-1 , prolyl-4-hydroxylase-2 , and ( in part ) placental growth factor , and hif-1-independent increased expression of angiopoietin - like 4 and prolyl-4-hydroxylase-1 . mfs can also directly respond to vegf and ang-1 , with vegf reported to elicit increased proliferation as well as increased synthesis of extracellular matrix components , and both vegf and ang-1 reported to stimulate oriented migration of hsc / mfs and mf - like cells from bone marrow - derived mesenchymal stem cells.30 , 86 , 87 hypoxia alone is able to induce oriented migration of either hsc / mfs or mf - like cells by eliciting a biphasic mechanism involving 1 ) an early phase of migration , switched on by mitochondria - released reactive oxygen species ( ros ) and requiring redox - dependent activation of extracellular - signal - regulated kinase and c - jun - nh2-terminal kinase isoforms ; and 2 ) a delayed and sustained phase of migration requiring the hif-1-mediated , ros - stabilized increased synthesis and release of vegf.29 , 30 , 86 , 87 overall these data fit well with morphologic evidence from both experimental rodent models of fibrosis and specimens from hepatitis c virus cirrhotic patients.29 , 30 positive staining for both hif-2 and heme oxygenase-1 has been reported in -sma positive mfs in developing septa and at the border of more mature and larger fibrotic septa . this scenario is similar to the previously described finding that expression of vegf , ang-1 , and related receptors vegf - r2 and tie2 was found at the leading edge of tiny and incomplete developing septa , but not in larger bridging septa . this suggests that pathologic angiogenesis during the fibrogenic progression of clds proceeds through two different phases : 1 ) an early phase , occurring in developing septa , in which fibrogenesis and angiogenesis are driven or modulated by hsc / mfs and by hypoxia itself ; and 2 ) a later phase , occurring in larger and more mature fibrotic septa , where chronic wound healing is likely to be less active and fibrogenic progression more established . morphologic analyses indicate that in the late setting proangiogenic factors , particularly receptors like vegf - r2 or tie2 , are expressed only by endothelial cells , a feature that should favor stabilization of the newly formed vessels . after exposure to hypoxia and proangiogenic mediators released by other hepatic cells , including hepatocytes , mfs may then migrate and align with the leading edge of developing fibrotic septa to drive at the same time fibrogenesis and pathologic angiogenesis , an attractive concept that fits well in the scenario of pathologic angiogenesis.88 , 89 , 90 angiogenesis is controlled by the balance between proangiogenic mediators ( eg , vegf ) and endogenous inhibitors of angiogenesis . pathologic angiogenesis can result from up - regulation of angiogenic stimuli and concurrent down - regulation of endogenous inhibitors , with a shift of the balance in favor of proangiogenic stimuli.88 , 89 , 90 this general view has been recently integrated , particularly for angiogenesis in clds , by an elegant study investigating the role of vasohibin . vasohibin is a natural antiangiogenic protein that is selectively induced in endothelial cells by vegf and appears to operate as an intrinsic , highly specific feedback inhibitor of activated endothelial cells engaged in the process of angiogenesis.91 , 92 expression profiling of vasohibin-1 and its relationship with vegf expression , angiogenesis , and fibrogenesis in animal models of cirrhosis and portal hypertension as well as in human cirrhotic liver specimens showed that vasohibin-1 and vegf are up - regulated in mesentery and liver in cirrhotic and precirrhotic portal hypertensive rats and cirrhotic patients . this suggests that vasohibin-1/vegf cascades are spatially and temporally coordinated through a negative - feedback loop driving pathologic angiogenesis through an overall positive effect on the activation of hscs and fibrogenic progression.24 , 92 paradoxically , the overexpression of vasohibin-1 by adenoviral gene transfer resulted in a significant reduction in pathologic angiogenesis , portal system collateralization , splanchnic blood flow , portohepatic resistance , and portal pressure as well as an attenuation in liver fibrogenesis that was attributed , at least in part , to a vasohibin-1-mediated inhibition of hsc activation.24 , 92 the investigators suggested that ectopic overexpression of vasohibin-1 , unlike endogenous expression of the protein , is not regulated by vegf and therefore can disrupt the negative - feedback loop , resulting in constant but lower levels of vegf synthesis ; this is believed to be sufficient to maintain vascular homeostasis but not pathologic angiogenesis.24 , 92 although several questions remain unanswered , this study is extremely promising particularly because overexpression of vasohibin-1 appeared to affect pathologic angiogenesis without acting on the normal liver vasculature . although hypoxia represents the most obvious proangiogenic environmental condition , the proangiogenic role of mfs is regulated and modulated by a number of other mediators and events typical of conditions of chronic injury and cld progression , including growth factors , oncogenes , cytokines , chemokines , metabolic or mitochondrial stress , and ros . most if not all of these mediators , although theoretically hypoxia - independent , result in either increased transcription of hif-1 mrna levels or ( as described for any condition leading to increased intracellular levels of ros ) increased stabilization of hif-1 . one example of a hypoxia - independent mediator is apelin , the endogenous ligand of angiotensin - like - receptor 1 ( apj ; agtrl1 ) . apelin and apj are expressed by mfs in cirrhotic animals and have been also detected in the splanchnic vasculature of portal hypertensive rats.48 , 93 , 94 interestingly , apelin synthesis by hsc / mfs is hypoxia - independent and up - regulated by angiotensin ii and et-1 ; moreover , recombinant apelin can directly stimulate collagen - i and pdgf receptor  ( pdgf - r ) expression in mf - like cells . as a proof of principle , experimental therapy based on the use of apelin receptor antagonists resulted in a significant reduction in liver angiogenesis and fibrosis as well as splanchnic angiogenesis and portosystemic collateral vessel formation.40 , 48 , 93 , 94 , 95 two other examples of hypoxia - independent mediators are leptin and pdgf ( particularly pdgf - bb ) . leptin is an adipocytokine that exerts a profibrogenic effect during the progression from nonalcoholic fatty liver disease ( nafld ) to nonalcoholic steatohepatitis ( nash).7 , 8 , 9 , 10 , 11 , 12 in human hsc / mfs , leptin up - regulates the expression of vegf and ang-1 as well as the proinflammatory chemokine ccl2 . the action of leptin on hsc / mfs is mediated through its binding to its receptors ( obesity receptor , obr ) and activation of several signaling pathways , including extracellular - signal - regulated kinase , akt , and nuclear factor-b , the latter relevant to chemokine expression . leptin also operates as a proangiogenic mediator through the recruitment and stabilization of hif-1 and the nuclear translocation of hif-1 . in  vivo experiments the proangiogenic role of leptin in nafld and nash was also confirmed by a study performed on zucker rats ( animals carrying leptin receptor mutations ) receiving the steatogenic choline - deficient and amino acid - defined diet . the role of pdgf ( known to stimulate proliferation and chemotaxis of mfs , particularly hsc / mfs ) as a proangiogenic mediator was first described by semela et  al . phenotype in hscs by modulating hsc - driven vascular tube formation in  vitro and enhanced coverage of sinusoids in  vivo , with resulting effects on vascular permeability and pressure regulation . proangiogenic signaling by pdgf required the involvement of the multifunctional ephrin - b2 receptor tyrosine kinase . pdgf and leptin have more recently been described as playing a proangiogenic role in human hsc / mfs by sharing a common signaling pathway that leads to up - regulation of vegf expression and release of the protein into the extracellular medium . this common signaling pathway involves activation of the mammalian target of rapamycin ( mtor ) pathway and generation of intracellular ros by nicotinamide adenine dinucleotide phosphate ( nadph)-oxidase , the latter event being relevant for increased hif-1 stabilization but not for the mammalian target of rapamycin ( mtor ) activation . finally , another potential role for pdgf was suggested by a study performed in myeloid cell - specific hif-1 or hif-1 knockout mice subjected to bile duct ligation , which suggested that a significant amount of pdgf produced in this experimental model was dependent on the activation of hifs in macrophages . microparticles ( mps ) are small plasma membrane vesicles surrounded by a phospholipid bilayer that are released by apoptotic or stressed cells and usually contain proteins derived from the parental cells . mps have been detected in various biological fluids , including peripheral blood and urine . in recent years , it has become clear that mps have important biological functions , including the horizontal transfer of bioactive molecules such as receptors , integrins , growth factors , rnas , and micrornas.100 , 101 circulating mps are increased in animal models of biliary cirrhosis and human cirrhosis and nash , and at least three different studies have linked the release of mps from hepatic cells to a proangiogenic effect in the setting of cld.102 , 103 , 104 , 105 although the cells releasing these proangiogenic mps were different depending on the form of liver disease , mps released by damaged or activated cells contributed significantly to pathologic angiogenesis regardless of their cell of origin . one study provided evidence that cholangiocytes and hsc / mfs can produce and then release ( mainly in response to pdgf ) mps containing hedgehog ( hh ) ligands . hh ligands activate hh signaling in endothelial cells , causing significant effects in the bile duct ligation model of fibrosis . this study found that in the normal liver the low levels of hh ligands released by immature ductular - type progenitors are efficiently counteracted by the expression of hh interacting protein ( hip ) expressed by either quiescent hscs or fenestrated lsecs . in conditions of chronic injury to biliary structures , however , hh interacting protein  expression is repressed , and the activation of ductular - type progenitor cells results in pdgf - bb up - regulation and release . pdgf - bb , in turn , induces hsc / mfs and ductular cells to produce and release hh ligands in mps ; these promote proliferation and survival of cholangiocytes and hsc / mfs as well as induce changes in lsec gene expression . overall , this results in capillarization of the sinusoids and the release of vasoactive factors such as no , contributing to vascular remodeling in cirrhosis . a second study , focused on the role of mps in nafld and nash , showed that hepatocytes exposed to conditions mimicking the lipid accumulation and lipotoxicity that occurs in the liver during forms of steatohepatitis can also release mps . these mps from fat - laden hepatocytes were found to act on endothelial cells and , after their internalization , to promote pathologic angiogenesis as shown in  vitro and in  vivo in mice exposed to a murine model of nafld / nash . of interest , large numbers of hepatocyte - derived mps were detected in the blood of mice with diet - induced steatohepatitis , and mps levels correlated with disease severity . genetic ablation of caspase-3 or rna interference directed against vanin-1 ( expressed on mps and mediating contact with lipid rafts of endothelial cells ) protected mice from steatohepatitis - induced pathologic angiogenesis and resulted in a loss of the proangiogenic effects of mps by reducing the extent of fibrosis . finally , a third study suggested that portal mfs release proangiogenic mps that contribute to the vascular changes leading to cirrhosis . expression of collagen , type xv , 1 ( col15a1 ) by portal mfs was markedly increased in human and rat liver tissue at advanced stages of fibrosis caused by either biliary or hepatocellular injury . in the cirrhotic liver , col15a1-expressing portal mfs were detected in an unusual perivascular distribution outlining vascular capillaries proximal to reactive ductules , within large fibrotic septa . portal mfs were found to release mps containing vegf - a ; this led to increased migration and tubulogenesis of lsecs and human umbilical vein endothelial cells and was able to trigger angiogenesis in matrigel plugs in mice . cholangiocytes potentiated the angiogenic properties of portal mfs by increasing vegf - a expression and mp shedding . this suggests that portal mfs have a significant role in angiogenesis and vascular remodeling , releasing vegf - a containing mp , acting as mural cells for newly formed vessels , and driving angiogenesis and scar progression from portal tracts into the parenchyma . the literature over the last decade has provided an unequivocal mechanistic link between liver angiogenesis and fibrogenesis . in the complex scenario of a progressive cld , several major issues predominate in the relationship between angiogenesis and fibrogenesis : 1 ) tissue hypoxia and cellular responses mediated by hifs significantly modulate the phenotype as well as migration and functional responses of all liver cells involved in cld progression ; 2 ) the interactions ( both direct or mediated through the release of several mediators or signals ) between hepatic cells are critical to both angiogenesis and fibrogenesis , with myofibroblasts serving a critical function integrating a variety of cell - derived signals ; and 3 ) mps have an important and increasingly appreciated role in mediating angiogenesis and vascular remodeling . future studies are needed to further unravel the molecular , cell , and tissue mechanisms linking angiogenesis and fibrogenesis ; ultimately , this has the potential to identify new targets for more selective and effective antifibrotic therapies .