Developmental Endothelial Locus-1 (Del-1), a Novel Angiogenic Protein

Abstract

Background-Developmentally regulated endothelial locus-1 (Del-1) is an extracellular matrix protein that is expressed by endothelial cells during embryological vascular development. We speculated that Del-1 may be reexpressed in ischemia and may be involved in endogenous angiogenesis. Methods and Results-Del-1 protein was detected by immunohistochemistry in murine ischemic hindlimb after femoral artery excision. To determine whether exogenous Del-1 would augment angiogenesis in vivo, Del-1 or vehicle was administered for 3 weeks by intramuscular injection of murine ischemic hindlimbs. Angiogenesis was quantified by gadolinium-MRI perfusion and capillary densitometry. We used a disc angiogenesis system (DAS) to characterize the angiogenic response to vehicle (PBS), Del-1, Del-1 mutant (altered RGD domain), Del-1 minor (truncated discoidin-I-like domain), or basic fibroblast growth factor. After 14 days, the discs were extracted and sectioned to quantify vascular growth by morphometry. Endogenous Del-1 protein expression was increased in ischemic hindlimbs. Administration of Del-1 increased hindlimb vascular flow index and capillary density. In the DAS, Del-1 doubled fibrovascular growth, as did basic fibroblast growth factor. However, angiogenesis was not enhanced by the Del-1 mutant or Del-1 minor proteins. Conclusions-Del-1 is expressed in ischemic tissue. Del-1 stimulates angiogenesis, an effect that is dependent on the RGD motif and a second signaling sequence in the discoidin-I-like domain. Exogenous intramuscular administration of Del-1 significantly enhances angiogenesis in the murine ischemic hindlimb. Del-1 may prove to be a novel therapeutic agent for patients with ischemia.

La lactadhérine, nouvel acteur de l’angiogenèse

“…L'activation des intégrines, même en l'absence de facteurs de croissance, peut affecter l'angiogenèse. Cela a notamment été démontré pour Del-1, l'analogue de la lactadhérine [3,4]. De même, nos travaux prouvent que la lactadhérine interagit avec les intégrines αvβ3 et αvβ5 et, par un mécanisme dépendant d'AKT, qu'elle est capable d'activer le développe-ment de nouveaux vaisseaux dans un contexte ischémique en l'absence de VEGF exogène ( Figure 2D).…”

“…La physiopathologie de l'infection reste mal comprise. La porte d'entrée est probablement respiratoire, aboutissant à une primo-infection pulmonaire souvent asymptomatique, puis la levure persisterait dans l'organisme sous une forme latente [3]. À la faveur d'une immunosuppression, la levure serait…”

“…Son rôle physiologique reste obscur. Elle est impliquée dans la reconnaissance des cellules apoptotiques par les macrophages [1,2], elle présente des homologies de séquence avec une protéine pro-angiogénique Del-1 et possède une séquence RGD lui permettant de se lier aux intégrines αvβ3 et αvβ5 [3,4]. L'ensemble de ces propriétés pouvait donc conférer à la lactadhérine un potentiel pro-angiogénique.…”

Aggregation of maternal pigment granules is induced by the cytosolic discoidin domain of theXenopus Del1 protein

“…Hypoxia was shown to increase Del1 expression in endothelial cells (Scheurer et al, 2004). Thus, Del1 acts as an angiogenic factor to stimulate vascularization (Penta et al, 1999;Ho et al, 2004). It has been suggested that Del1 may also have a role in the angiogenic remodeling of vascular tissue after ischemic damage (Ho et al, 2004).…”

“…Thus, Del1 acts as an angiogenic factor to stimulate vascularization (Penta et al, 1999;Ho et al, 2004). It has been suggested that Del1 may also have a role in the angiogenic remodeling of vascular tissue after ischemic damage (Ho et al, 2004). Del1 promotes solid tumor expansion by inducing endothelial cell formation, which leads to the suppression of tumor apoptosis by increasing blood flow supply (Aoka et al, 2002).…”