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Endoglin involvement in integrin-mediated cell adhesion as a putative pathogenic mechanism in hereditary hemorrhagic telangiectasia type 1 (HHT1).

Rossi E, Lopez-Novoa JM, Bernabeu C - Front Genet (2015)

Bottom Line: Because of the absence of effective treatments for HHT symptoms, studies aimed at identifying novel biological functions of endoglin which could serve as therapeutic targets of the disease are needed.Endoglin displays, within its zona pellucida domain, an RGD motif, which is a prototypic sequence involved in integrin-based interactions with other proteins.In addition, functional, as well as protein and gene expression analysis have shown that ectopic endoglin represses the synthesis of several members of the integrin family and modulates integrin-mediated cell adhesions.

View Article: PubMed Central - PubMed

Affiliation: INSERM, Faculté des Sciences Pharmaceutiques et Biologiques, Université Paris Descartes, UMR-S 1140 Paris, France.

ABSTRACT
Mutations in the endoglin gene (ENG) are responsible for ∼50% of all cases with hereditary hemorrhagic telangiectasia (HHT). Because of the absence of effective treatments for HHT symptoms, studies aimed at identifying novel biological functions of endoglin which could serve as therapeutic targets of the disease are needed. Endoglin is an endothelial membrane protein, whose most studied function has been its role as an auxiliary receptor in the TGF-β receptor complex. However, several lines of evidence suggest the involvement of endoglin in TGF-β-independent functions. Endoglin displays, within its zona pellucida domain, an RGD motif, which is a prototypic sequence involved in integrin-based interactions with other proteins. Indeed, we have recently described a novel role for endothelial endoglin in leukocyte trafficking and extravasation via its interaction with leukocyte integrins. In addition, functional, as well as protein and gene expression analysis have shown that ectopic endoglin represses the synthesis of several members of the integrin family and modulates integrin-mediated cell adhesions. This review focuses on the tight link between endoglin and integrins and how the role of endothelial endoglin in integrin-dependent cell adhesion processes can provide a better understanding of the pathogenic mechanisms leading to vascular lesions in endoglin haploinsufficient HHT1 patients.

No MeSH data available.


Related in: MedlinePlus

Hypothetical model for the generation of arteriovenous malformations in HHT. In healthy subjects, the capillary network subjected to an inflammatory stimulus is infiltrated with leukocytes that contribute to the vascular repair/remodeling. As a consequence the capillary network is restored. In HHT1 patients, endoglin haploinsufficiency impairs leukocyte adhesion/transmigration, leading to a defective vascular repair/remodeling. As a consequence, the capillary network gradually disappears and only a preferential vessel remains that eventually becomes the arteriovenous shunt.
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Figure 2: Hypothetical model for the generation of arteriovenous malformations in HHT. In healthy subjects, the capillary network subjected to an inflammatory stimulus is infiltrated with leukocytes that contribute to the vascular repair/remodeling. As a consequence the capillary network is restored. In HHT1 patients, endoglin haploinsufficiency impairs leukocyte adhesion/transmigration, leading to a defective vascular repair/remodeling. As a consequence, the capillary network gradually disappears and only a preferential vessel remains that eventually becomes the arteriovenous shunt.

Mentions: A common feature in HHT patients is the presence of vascular lesions (telangiectasias and arteriovenous malformations) that lead to a loss of the intervening capillary network that connects the arteriole with the venule (Braverman et al., 1990). However, it remains unclear why the vascular lesions appear only at distinct sites within certain organs, rather than being present throughout the body and in all organs/tissues. To explain this paradox, the need for a trigger such as inflammation, vascular injury, angiogenic stimuli, or ischemia has been postulated (Park et al., 2009; López-Novoa and Bernabeu, 2010; Choi et al., 2014). In HHT1, this trigger would synergize with endoglin haploinsufficiency to generate the vascular lesion (Lopez-Novoa, 2012; Choi et al., 2014). Interestingly, those stimuli are usually associated with the upregulated expression of endoglin in endothelial cells and an inflammatory cell infiltrate (Torsney et al., 2002; López-Novoa and Bernabeu, 2010), suggesting the need of both, endoglin function and leukocyte infiltration, in the vascular repair/remodeling process. Indeed, it has been reported that endoglin plays a crucial role in leukocyte-mediated vascular repair (van Laake et al., 2006). Of note, HHT skin telangiectasias show a perivascular mononuclear cell infiltrate, including lymphocytes and monocytes/macrophages (Braverman et al., 1990). This is in agreement with the leukocyte infiltration occurring during angiogenesis and vascular remodeling (Jaipersad et al., 2014). Therefore, it can be hypothesized that the function of endothelial endoglin as an adhesion counter-receptor for leukocyte’s integrins is involved in HHT1 pathogenesis (Figure 2). According to this hypothetical model, in healthy subjects the capillary network subjected to an inflammatory stimulus is infiltrated with leukocytes that contribute to the vascular repair/remodeling. By contrast, in HHT1 patients endoglin haploinsufficiency impairs leukocyte infiltration, leading to a defective vascular repair/remodeling. As a consequence, the capillary network would disappear and only a preferential vessel remains that eventually becomes the arterio-venous shunt.


Endoglin involvement in integrin-mediated cell adhesion as a putative pathogenic mechanism in hereditary hemorrhagic telangiectasia type 1 (HHT1).

Rossi E, Lopez-Novoa JM, Bernabeu C - Front Genet (2015)

Hypothetical model for the generation of arteriovenous malformations in HHT. In healthy subjects, the capillary network subjected to an inflammatory stimulus is infiltrated with leukocytes that contribute to the vascular repair/remodeling. As a consequence the capillary network is restored. In HHT1 patients, endoglin haploinsufficiency impairs leukocyte adhesion/transmigration, leading to a defective vascular repair/remodeling. As a consequence, the capillary network gradually disappears and only a preferential vessel remains that eventually becomes the arteriovenous shunt.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4285797&req=5

Figure 2: Hypothetical model for the generation of arteriovenous malformations in HHT. In healthy subjects, the capillary network subjected to an inflammatory stimulus is infiltrated with leukocytes that contribute to the vascular repair/remodeling. As a consequence the capillary network is restored. In HHT1 patients, endoglin haploinsufficiency impairs leukocyte adhesion/transmigration, leading to a defective vascular repair/remodeling. As a consequence, the capillary network gradually disappears and only a preferential vessel remains that eventually becomes the arteriovenous shunt.
Mentions: A common feature in HHT patients is the presence of vascular lesions (telangiectasias and arteriovenous malformations) that lead to a loss of the intervening capillary network that connects the arteriole with the venule (Braverman et al., 1990). However, it remains unclear why the vascular lesions appear only at distinct sites within certain organs, rather than being present throughout the body and in all organs/tissues. To explain this paradox, the need for a trigger such as inflammation, vascular injury, angiogenic stimuli, or ischemia has been postulated (Park et al., 2009; López-Novoa and Bernabeu, 2010; Choi et al., 2014). In HHT1, this trigger would synergize with endoglin haploinsufficiency to generate the vascular lesion (Lopez-Novoa, 2012; Choi et al., 2014). Interestingly, those stimuli are usually associated with the upregulated expression of endoglin in endothelial cells and an inflammatory cell infiltrate (Torsney et al., 2002; López-Novoa and Bernabeu, 2010), suggesting the need of both, endoglin function and leukocyte infiltration, in the vascular repair/remodeling process. Indeed, it has been reported that endoglin plays a crucial role in leukocyte-mediated vascular repair (van Laake et al., 2006). Of note, HHT skin telangiectasias show a perivascular mononuclear cell infiltrate, including lymphocytes and monocytes/macrophages (Braverman et al., 1990). This is in agreement with the leukocyte infiltration occurring during angiogenesis and vascular remodeling (Jaipersad et al., 2014). Therefore, it can be hypothesized that the function of endothelial endoglin as an adhesion counter-receptor for leukocyte’s integrins is involved in HHT1 pathogenesis (Figure 2). According to this hypothetical model, in healthy subjects the capillary network subjected to an inflammatory stimulus is infiltrated with leukocytes that contribute to the vascular repair/remodeling. By contrast, in HHT1 patients endoglin haploinsufficiency impairs leukocyte infiltration, leading to a defective vascular repair/remodeling. As a consequence, the capillary network would disappear and only a preferential vessel remains that eventually becomes the arterio-venous shunt.

Bottom Line: Because of the absence of effective treatments for HHT symptoms, studies aimed at identifying novel biological functions of endoglin which could serve as therapeutic targets of the disease are needed.Endoglin displays, within its zona pellucida domain, an RGD motif, which is a prototypic sequence involved in integrin-based interactions with other proteins.In addition, functional, as well as protein and gene expression analysis have shown that ectopic endoglin represses the synthesis of several members of the integrin family and modulates integrin-mediated cell adhesions.

View Article: PubMed Central - PubMed

Affiliation: INSERM, Faculté des Sciences Pharmaceutiques et Biologiques, Université Paris Descartes, UMR-S 1140 Paris, France.

ABSTRACT
Mutations in the endoglin gene (ENG) are responsible for ∼50% of all cases with hereditary hemorrhagic telangiectasia (HHT). Because of the absence of effective treatments for HHT symptoms, studies aimed at identifying novel biological functions of endoglin which could serve as therapeutic targets of the disease are needed. Endoglin is an endothelial membrane protein, whose most studied function has been its role as an auxiliary receptor in the TGF-β receptor complex. However, several lines of evidence suggest the involvement of endoglin in TGF-β-independent functions. Endoglin displays, within its zona pellucida domain, an RGD motif, which is a prototypic sequence involved in integrin-based interactions with other proteins. Indeed, we have recently described a novel role for endothelial endoglin in leukocyte trafficking and extravasation via its interaction with leukocyte integrins. In addition, functional, as well as protein and gene expression analysis have shown that ectopic endoglin represses the synthesis of several members of the integrin family and modulates integrin-mediated cell adhesions. This review focuses on the tight link between endoglin and integrins and how the role of endothelial endoglin in integrin-dependent cell adhesion processes can provide a better understanding of the pathogenic mechanisms leading to vascular lesions in endoglin haploinsufficient HHT1 patients.

No MeSH data available.


Related in: MedlinePlus