Journal of Hepatology
Volume 43, Issue 1 , Pages 6-8, July 2005

VEGF-induced angiogenesis drives collateral circulation in portal hypertension

  • Richard Moreau

      Affiliations

    • Corresponding Author InformationTel.: +33 1 40 87 55 13; fax: +33 1 47 30 94 40.

Laboratoire d'Hémodynamique Splanchnique et de Biologie Vasculaire, INSERM, and Service d'Hépatologie, Hôpital Beaujon, F-92118 Clichy, France

published online 26 April 2005.

See Article, pages 98--103

Article Outline

 

Portal hypertension is a complication of diseases such as cirrhosis or portal vein thrombosis which cause an obstacle to portal blood flow [1]. Portal hypertension is associated with the development of a portal-systemic collateral circulation, which decompresses the portal vascular system. Gastroesophageal varices develop in collateral vessels and these varices may rupture causing severe hemorrhage. In addition, the portal-systemic collateral circulation may favour the irruption in the systemic circulation of gut-derived substances causing encephalopathy, sepsis, or pulmonary hypertension. Thus, the portal-systemic collateral circulation plays a crucial role in the mechanisms of several complications of portal hypertension that often cause death. Until recently, it was thought that the development of collateral circulation was due to the passive opening of vascular channels in response to increased portal pressure. However, this ‘traditional’ view has been recently challenged by the results of two studies by Fernandez et al. [2], [3] from Barcelona showing that the formation of portal-systemic circulation may be, at least in part, due to angiogenesis driven by vascular endothelial growth factor (VEGF). One of these studies is published in this issue of the Journal [3].

Before commenting on these two studies, it is important to have in mind some definitions. During embryonic development, vasculogenesis (i.e. the formation of a primary vascular plexus by differentiation of angioblasts) precedes sprouting and non-sprouting angiogenesis (i.e. the formation of new vascular channels from pre-existing vessels) [4]. Angiogenesis also occurs in the adult; it contributes to a number of physiological processes such as wound healing and reproductive cycling [5]. Nitric oxide (NO)-induced dilatation and increased permeability of existing vessels as well as migration, proliferation and survival of mature endothelial cells, all play a crucial role in angiogenesis [6].

Many molecules have been implicated as positive regulators of angiogenesis, including VEGF (also known as VEGF-A), acidic fibroblast growth factor (FGF), basic FGF, transforming growth factor (TGF)-α, TGF-β, hepatocyte growth factor, tumor necrosis factor-α, angiogenin, interleukin (IL)-8 and the angiopoietins [6], [7], [8]. Of all the known angiogenic molecules, VEGF appears the most critical. Indeed, VEGF stimulates NO production by endothelial NO synthase and increases vascular permeability [6], [7], [8]. More importantly, VEGF induces the migration, proliferation and survival of endothelial cells, increases the display of adhesion molecules on these cells [7].

Several mechanisms induce the VEGF gene (VEGF). Logically, hypoxia stimulates angiogenesis [6]. Hypoxia, via hypoxia-inducible transcription factors, increases VEGF protein levels by stimulating VEGF transcription and increasing VEGF mRNA stability. Moreover, an internal ribosomal entry site allows preserved translation in the face of cellular hypoxic shutdown. Growth factors, including epidermal growth factor, TGF-α, TGF-β, keratinocyte growth factor, insulin-like growth factor-1, FGF and platelet-derived growth factor, also upregulate VEGF mRNA expression. The proinflammatory cytokines IL-1α and IL-6 also induce VEGF expression.

VEGF is alternatively transcribed in several isoforms with different extracellular matrix (ECM)-binding affinities (reviewed in Ref. [7]): the diffusible VEGF120, which lacks the heparin-binding domain that is necessary for interaction with the ECM; the VEGF188 isoform, which is secreted but remains bound to ECM and is not soluble; and the VEGF164 isoform, which has intermediary properties as it is secreted but a significant fraction remains bound to ECM. Genetic studies in knock-in mice that express a single VEGF isoform have provided insights on how VEGF, through the localization of heparin-binding isoforms in the extracellular matrix, provides a gradient of branching and patterning cues. In VEGF164/164 mice, which express only the VEGF164 isoform, vascular guidance is normal, indicating that this isoform confers all guidance cues for vessel patterning [9]. In VEGF120/120 mice, which express only the VEGF120 isoform, vascular guidance is abnormal. The freely diffusible VEGF120 is chaotically distributed and fails to provide a directional long-range guidance clue. Thus, endothelial cells in a single vessel move in all directions, which leads to vessel expansion rather than directional branching [9], [10], [11], [12]. Interestingly, loss of the heparin-binding domain results in a significant decrease in the mitogenic activity of VEGF [11]. In VEGF188/188 mice, which express only the VEGF188 isoform, there is no long-range attraction and endothelial cells are misguided over short distances, often taking wrong turns [9].

On the cell surface of vascular endothelial cells, VEGF may bind two related receptor tyrosine kinases (RTKs), VEGFR-1 (also known as Flt-1) and VEGFR-2 (also known as kinase domain region KDR or Flk-1) [5], [6], [7], [8], [13]. In addition to these RTKs, VEGF interacts with a coreceptor, neuropilin-1. All VEGF isoforms bind VEGFR-1 and -2, but only VEGF164 binds neuropilin-1. It is clear that VEGFR-2 is the major mediator of the angiogenic effects of VEGF. Neuropilin-1 binding by VEGF164 results in enhanced VEGFR-2 signalling. The functions of VEGFR-1 are poorly understood [7]. Interestingly, placental growth factor (PlGF, a homologue of VEGF), which binds VEGFR-1 enhances angiogenesis, but under pathological conditions [14]. PlGF increases VEGF-driven angiogenesis via a unique cross-talk between VEGFR-1 and -2 [15].

Many diseases (e.g. cancers, psoriasis or allergic lung inflammation) are associated with increased VEGF-induced angiogenesis (reviewed in Ref. [6]). The findings by Fernandez et al. [2], [3] indicate that portal hypertension should be added to this list of diseases. First, they found a time-dependent increase in CD31 (also known as PECAM-1) protein levels in the duodenum, intestine and mesentery from portal vein-stenosed mice [2]. CD31 is expressed at the endothelial cell surface and homotypic endothelial cell contacts through CD31 play a crucial role in angiogenesis [6]. In addition, in portal vein-stenosed mice, there was a time-dependent increase in the protein levels of VEGF and VEGFR-2 in different splanchnic territories [2]. Interestingly, similar increases in protein levels of CD31, VEGF, and VEGFR-2 were found in the mesentery from portal vein-stenosed rats [3]. Finally, the implication of VEGF/VEGFR2 pathway in the formation of collateral circulation was supported by the results obtained with VEGFR-2 blockade (using an anti-VEGFR-2 monoclonal antibodies for 5–7 days after surgery, in mice) [2] or with inhibition of VEGFR-2 signaling (using an inhibitor of VEGFR-2 autophosphorylation for 5 days after surgery, in rats) [3]. These two pharmacological approaches resulted in a 50% decrease in the formation of portal-systemic collateral blood vessels in mice or rats with portal vein stenosis. Moreover, both treatments induced a significant decrease in the splanchnic protein levels of CD31, and VEGFR-2.

Fernandez et al. [3] also found that, in portal vein-stenosed rats, a 5-day inhibition of VEGFR-2 signaling resulted in a significant decrease in portal venous inflow and increases in splanchnic arteriolar resistance and portal venous resistance. On the other hand, the administration of a single dose of the VEGFR-2 inhibitor 7 days after surgery (i.e. when the hyperkinetic syndrome is fully established) did not elicit any significant changes in splanchnic and systemic haemodynamics, indicating that the VEGFR-2 inhibitor does not act directly on the arteriolar tone [3]. Interestingly, decreased VEGF levels have been found in systemic arterial walls from portal hypertensive rats [16]. Together, these findings suggest that the VEGF/VEGFR-2 pathway contributes to the development of portal-systemic collateral vessels and hyperdynamic splanchnic circulation in portal hypertensive animals.

Was the pharmacological approach used by Fernandez et al. more appropriate than genetic studies to investigate the in vivo inhibition of the VEGF/VEGFR-2 pathway? The answer is yes since most knockout mice die pre- or perinatally (reviewed in Ref. [5]). In addition, genetic studies show that 50% of the mice expressing exclusively VEGF120 die shortly after delivery, whereas the remainder die within 2 weeks [9].

The stimuli of VEGF overexpression in portal hypertension have not yet been identified. There are several candidates for this (see above). In addition, blood flowing through collateral vessels may have proangiogenic effects by increasing shear stress [4], [5], [6], [8].

The studies by Fernandez et al. raise other questions. What is (are) the VEGF isoform(s) overexpressed in the collateral circulation? Do collateral vessels express VEGF binding sites other than VEGFR-2? Are other proangiogenic factors involved in the development of collateral circulation? Clearly, further studies are needed.

In conclusion, in portal hypertensive animals, VEGF-induced, VEGFR-2-mediated angiogenesis seems to play an important role in the formation of portal-systemic collateral circulation and splanchnic hyperdynamic circulation. Thus, inhibition of VEGF-driven angiogenesis may be a novel approach to prevent the formation of collateral circulation in patients who are at risk of developing this complication of portal hypertension.

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References 

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  3. Fernandez M, Mejias M, Angermayr B, Garcia-Pagan JC, Rodés J, Bosch J. Inhibition of VEGF receptor-2 decreases the development of hyperdynamic splanchnic circulation and portal-systemic collateral vessels in portal hypertensive rats. J Hepatol. 2005;43:98–103
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PII: S0168-8278(05)00259-X

doi:10.1016/j.jhep.2005.04.002

Journal of Hepatology
Volume 43, Issue 1 , Pages 6-8, July 2005

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