What we do …


The major aims of our team are:

  • To understand the function and regulation/dysregulation of angiogenesis in chronic liver disease.

  • To explore the pathogenic mechanisms and impact of obesity on chronic liver disease.

  • To decipher the major disease-relevant pathways in the progression from liver steatosis to cirrhosis and liver cancer.

  • To apply our knowledge and research discoveries on the fundamental cell biology/pathophysiology of liver disease to the comprehension, prevention or treatment of human pathologies.

To achieve these goals, we take a multidisciplinary approach that employs in vivo studies in animal models of liver disease and genetically engineered mouse models, cellular and molecular biology analyses, biochemistry techniques, strategies in primary cell cultures and established mammalian cell lines and human tissues, to systematically dissect the pathologic signaling pathways of interest which could be therapeutically targeted to improve human health.

Angiogenesis

Angiogenesis refers to new microvessel formation via sprouting or splitting from preexisting vessels. Upon exposure to proangiogenic signals like vascular endothelial growth factor (VEGF), endothelial cells activate, become mobile and protrude filopodia, forming tip cells, which initiate new sprouts. Stalk cells follow tip cells, proliferate to support sprout elongation, and establish a vessel lumen. Microvessel loops are then formed when tip cells anastomose with neighbouring sprouts. After the microvessel forms a lumen, endothelial cells secrete growth factors, such as platelet-derived growth factor (PDGF), to attract pericytes and smooth muscle cells that stabilize the nascent vessel. Endothelial cells and pericytes become sensitized to the chemotactic and proliferative effects of the various growth factors by upregulating their receptors, predominantly VEGF receptor-2 and PDGF receptor-beta (Read More).

angiogenesis mercedes fernandez labs
Figreview1

Angiogenesis in liver disease

Abnormal neovessel formation represents a critical and clinically important hallmark feature of chronic liver diseases, such as liver cirrhosis and liver cancer, for which few therapeutic options are available. Recognition of the importance of angiogenesis in the pathophysiology of chronic liver disease is relatively recent, and was given particular impetus by the observation that the proangiogenic growth factor VEGF and its signaling pathway is switched on and promotes an extensive VEGF-driven neovascularization in the mesenteric vascular bed during liver cirrhosis, thereby contributing to the development of increased splanchnic blood flow (Read More), working in a cooperative fashion with splanchnic vasodilatation, and aggravating portal hypertension (Read More). Pathological angiogenesis is also behind the establishment and maintenance of the abnormal angioarchitecture distinctive of the cirrhotic liver, being functionally linked with fibrogenesis and inflammation. Accordingly, diminishing pathological angiogenesis has multiple beneficial effects in chronic liver disease (Read More).

Angiogenesis, collaterals and varices

Importantly, VEGF-dependent angiogenesis also plays a crucial part in the formation of portosystemic collateral vessels and gastroesophageal varices (Read More). These varices are fragile and particularly prone to leak blood and even rupture, causing upper gastrointestinal tract bleeding. This hemorrhage is often torrential and difficult to staunch, and, despite many advances made in this field, it continues to be the cause of significant morbidity and mortality in patients. Furthermore, because portosystemic venous shunts bypass the liver, noxious substances that are normally metabolized by the liver can escape from collaterals to the central venous system, leading to other potentially lethal consequences, such as portosystemic encephalopathy, spontaneous bacterial peritonitis or systemic infections.

17999583_ml
Foto-coculture

Angiogenesis is not always a bad thing

Therapeutic targeting of angiogenesis has been proposed as a promising strategy for liver disease. However, the clinical benefit of antiangiogenic drugs is restricted because of significant adverse effects, including collapse of normal vasculature, vascular leakage and bleeding, as exemplified in patients with hepatocellular carcinoma and cirrhosis. Most of these limitations arise from the fact that current anti-VEGF approaches are not selective for pathological VEGF production, but instead inhibit also physiological VEGF required for vascular homeostasis of healthy vessels and formation of vascular supply in many physiological settings. Deciphering mechanisms that regulate VEGF expression is therefore critical to achieve specific inhibition of pathological generation of VEGF without affecting its physiological production. This is a major goal of our research.

CPEB proteins regulate pathologic VEGF expression and angiogenesis

In a search for ways to inhibit pathologic production or activities of VEGF without affecting its normal production or functions, we have investigated the post-transcriptional regulation of VEGF by the cytoplasmic polyadenylation element-binding proteins CPEB1 and CPEB4 during development of liver disease. We have identified a mechanism of VEGF overexpression in liver and mesentery that promotes pathologic, but not physiologic, angiogenesis, via sequential and non-redundant functions of CPEB1 and CPEB4. Activation of CPEB1 promotes alternative nuclear processing within non-coding 3′-untranslated regions of VEGF and CPEB4 mRNAs, resulting in deletion of translation repressor elements. The subsequent overexpression of CPEB4 promotes cytoplasmic polyadenylation of VEGF mRNA, increasing its translation and generating high levels of VEGF protein, which induces pathologic angiogenesis in chronic liver disease (Read More).

CPEB proteins fernandez labs
fotomodelocpeb

CPEB proteins as targets for therapy

From a translational point of view, our studies highlight that CPEBs could be promising angiogenesis-disrupting targets in disease. Thus, targeting CPEBs could lead to safer treatment outcomes by specifically reducing excessive pathological VEGF production instead of indiscriminately perturbing both pathological and physiological VEGF synthesis, minimizing potential adverse side-effects. Reduction of pathological angiogenesis in early disease stages could also prevent further disease progression and reduce the risk for developing overt liver cirrhosis. Accordingly, development and evaluation of CPEB inhibitors is currently underway. As better and more specific inhibitors of pathologic angiogenesis are developed, combination strategies continue to evolve, and increased understanding of the complex biology of angiogenesis takes place, antiangiogenic therapy will certainly be evaluated in future clinical trials (Read More).

Vascular stem cells, new culprits uncovered 

Recent studies from our lab highlight the functional significance of pathologic neovascularization derived from vascular stem/progenitor cells as an important mechanism of formation of new blood vessels in adults, in the setting of chronic liver disease, and identifies these stem cells as potential new therapeutic targets. Thus, we have demonstrated the existence in the vascular wall of adult mesenteric blood vessels of a distinctive population of vascular stem/progenitor cells. These cells display some of the most widely accepted criteria for stem cell recognition, including quiescence and slow-cycling properties, high proliferative potentiality, capability of growing as cellular spheres in suspension culture, expression of specific biomarkers of stem cells, and the ability to self-renew and generate daughter cells in response to liver disease induction. This vascular stem cell progeny is able to differentiate into endothelial and smooth muscle cell lineages, and readily contribute physically and functionally to neovascularization in vivo during chronic liver disease. Hence, chronic liver disease-associated abnormal neovascularization might conceivably be a heterogeneous process, arising through a combination of both neoangiogenesis and neovasculogenesis. Accordingly, therapeutic targeting of both vascular stem cell-derived neovascularization (vasculogenesis) and new vessel growth mechanisms that utilize non-stem cell constituents (angiogenesis) may effectively block abnormal neovessel formation and improve antiangiogenic therapeutics (Read More).

Vascular stem cells
29114856_ml

Hepatocellular carcinoma

Hepatocellular carcinoma is the most common type of liver cancer and a leading cause of death worldwide. Most cases of hepatocellular carcinoma develop in a liver previously affected by chronic liver damage such as fibrosis and cirrhosis, which, in turn, can be caused by excessive alcohol consumption, viral hepatitis, and non-alcoholic obesity-induced fatty liver disease (hepatic steatosis or NAFLD). In fact, these fibrotic/cirrhotic changes are almost a pre-requisite for the formation of hepatocellular carcinoma. This ultimately makes hepatocellular carcinoma a disease with two distinct components (i.e., liver dysfunction and malignancy) that have to be addressed when developing novel therapeutic strategies.

Transition to liver cancer

Liver cancer incidence has more than tripled since 1980 on a worldwide scale, mostly due to the global epidemic of obesity, which is also sharply rising all over the world. Despite this growing incidence, the management of these patients continues to be a critical and prevalent clinical problem, for which few therapeutic options are available beyond resection, ablation or liver transplantation. Consequently, novel treatment strategies are urgently needed to improve the therapeutic outcome of patients suffering from hepatocellular carcinoma. And for that, it is essential to understand more precisely which are the pathogenic processes involved in the progression of chronic liver disease, from simple steatosis to fibrosis and liver cancer, and most importantly, which are the molecular mechanisms responsible for this progression. This is a major goal of our research.

fotohumanliverweb
Figure Vessels

Vasohibin, new feedback inhibitor of angiogenesis

Vasohibin-1 is a recently identified endogenous inhibitor of angiogenesis that is selectively induced by the proangiogenic growth factor VEGF as a consequence of a specific negative-feedback regulator mechanism of pathological angiogenesis in cirrhosis. As we have seen, ectopical, and non-VEGF regulated, vasohibin-1 overexpression by adenoviral-mediated gene transfer leads to disruption of the VEGF-vasohibin-1 negative-feedback loop, dampening VEGF production to intermediate steady-state levels sufficient to maintain vascular homeostasis or physiological angiogenesis associated with wound healing, but not to drive pathological angiogenesis. This effect translated into efficient suppression of mesenteric and intrahepatic pathological neovascularization and reduction of portal pressure and portosystemic collateral vessel formation in cirrhotic rats, without any apparent adverse side effect. The protective action of overexpressing VASH1 protein in vivo by gene therapy with an adenoviral vector encoding VASH1 was not restricted to inhibition of angiogenesis, but included a potent ability to attenuate intrahepatic fibrogenesis through suppression of hepatic stellate cell activation. These results strongly suggest that supplementation with VASH1 might be a novel and promising therapeutic strategy for halting chronic liver disease progression (Read More).

Pigment epithelium-derived factor, protective factor with therapeutic potential

Pigment epithelium derived factor (PEDF) is one of the strongest natural inhibitors of pathological angiogenesis known to date, and this property has turned it into a promising therapeutic tool for slowing the progression of many neovascular pathologies. Recent studies from our research group demonstrate that both the negative regulator of angiogenesis PEDF and the angiogenesis inducer VEGF are unidirectionally upregulated in mesentery and liver in experimental models of cirrhosis, being closely linked in time and space with mesenteric neovascularization and liver fibrogenesis, suggesting that PEDF induction might reflect a compensatory mechanism aimed at reducing the adverse effects of VEGF. Exogenous PEDF overexpression by adenovirus-mediated gene transfer moves the balance between VEGF and PEDF in favor of inhibition and angiogenesis, translating into portal pressure decrease and partial correction of excessive angiogenesis in experimental cirrhosis. Therefore, exogenous PEDF supplementation could be a promising and plausible therapeutic modality for preventing further disease progression and consequently reducing the risk for developing overt liver cirrhosis in patients. Of note, targeting early pathogenic changes might afford an opportunity to intervene on chronic liver disease at a stage before irreversible fibrosis. Another prominent advantage of using angioinhibitors that are endogenously present in the body, such as PEDF, is that these molecules would not be expected to activate drug resistant genes and, thus, may offer a promising breakthrough for effective antiangiogenesis therapy (Read More).

fotovasos-low

Uso de cookies

Este sitio web utiliza cookies para que usted tenga la mejor experiencia de usuario. Si continúa navegando está dando su consentimiento para la aceptación de las mencionadas cookies y la aceptación de nuestra política de cookies, pinche el enlace para mayor información.plugin cookies

ACEPTAR
Aviso de cookies