Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0021933 (intussusception)
 3,822 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Vascular endothelial growth factor (VEGF) is expressed in human endometrium, but the cellular source of VEGF for endometrial angiogenesis has not been determined. In the present study the relationship between focal VEGF associated with microvessels and endothelial cell proliferation was examined in three layers of human endometrium at various stages of the menstrual cycle (menstrual, proliferative and secretory). Immunohistochemical analysis of full thickness endometrium from 18 hysterectomy samples without endometrial pathology were examined. The percentage of proliferating vessels was higher in proliferative compared to secretory endometrium, but this was only statistically significant in the basalis layer. A significantly greater percentage of VEGF-expressing microvessels was observed in proliferative than secretory endometrium (P < 0.05). The most VEGF-expressing microvessels were observed in the subepithelial capillary plexus, followed by the functionalis and least were present in the basalis. There was a significant correlation between focal VEGF-expressing microvessels and proliferating vessels for the subepithelial capillary plexus (R(s) = 0.70, P = 0.008), the functionalis (R(s) = 0.70, P = 0.001) and the basalis (R(s) = 0.76, P < 0.001). Focal VEGF associated with microvessels was found in marginating and adherent neutrophils. These data suggest that neutrophils in intimate contact with endometrial endothelium may be a source of intravascular VEGF for vessels undergoing angiogenesis by elongation or intussusception, particularly during the proliferative phase of rapid endometrial growth.
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PMID:Focal vascular endothelial growth factor correlates with angiogenesis in human endometrium. Role of intravascular neutrophils. 1138 70

Vascular endothelial growth factor (VEGF) is the master regulator of angiogenesis, whose best-understood mechanism is sprouting. However, therapeutic VEGF delivery to ischemic muscle induces angiogenesis by the alternative process of intussusception, or vascular splitting, whose molecular regulation is essentially unknown. Here, we identify ephrinB2/EphB4 signaling as a key regulator of intussusceptive angiogenesis and its outcome under therapeutically relevant conditions. EphB4 signaling fine-tunes the degree of endothelial proliferation induced by specific VEGF doses during the initial stage of circumferential enlargement of vessels, thereby limiting their size and subsequently enabling successful splitting into normal capillary networks. Mechanistically, EphB4 neither inhibits VEGF-R2 activation by VEGF nor its internalization, but it modulates VEGF-R2 downstream signaling through phospho-ERK1/2. In vivo inhibitor experiments show that ERK1/2 activity is required for EphB4 regulation of VEGF-induced intussusceptive angiogenesis. Lastly, after clinically relevant VEGF gene delivery with adenoviral vectors, pharmacological stimulation of EphB4 normalizes dysfunctional vascular growth in both normoxic and ischemic muscle. These results identify EphB4 as a druggable target to modulate the outcome of VEGF gene delivery and support further investigation of its therapeutic potential.
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PMID:EphrinB2/EphB4 signaling regulates non-sprouting angiogenesis by VEGF. 2964 20