Shortened ALK1 regulatory fragment maintains a specific activity in arteries feeding ischemic tissues.
Specific transgene induction in angiogenic blood vessels has been in demand in gene therapies for several cardiovascular and malignant proliferative diseases in which the vasculature is an essential part of the disease process. In addition to improvements of delivery vehicles, promoters specific to angiogenic blood vessels have been sought for driving expression of the therapeutic gene. Earlier, we isolated a mouse activin receptor-like kinase 1 (Alk1; Acvrl1) transcriptional regulatory fragment that specifically induces transgene expression in newly forming and remodeling arteries in tumor and wound-healing lesions. For the purpose of gene therapy, however, this 9.2 kb regulatory fragment is too large to be incorporated into most viral transfer vectors. To bypass this limitation, highly conserved regions within the Alk1 gene were used to generate a shortened regulatory fragment. In transgenic mice, the shortened 4.8 kb Alk1PIB fragment showed comparable specificities in angiogenic and remodeling feeding arteries. In addition, the Alk1PIB fragment in a recombinant adenovirus vector showed transcriptional activity in cultured human iliac arterial endothelial cells (HIAECs). The Alk1PIB fragment may be used to target therapeutic protein expression in the feeding arteries to assist in the regeneration of ischemic tissues or to induce damages to the lesions, such as malignant tumors.
Department of Physiology, Medical College of Georgia, Augusta, GA 30912, USA.
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Li
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Yonenaga
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D030201:Activin Receptors, Type I / Q000235:genetics*; D030301:Activin Receptors, Type II; D000818:Animals; D001158:Arteries / Q000378:metabolism*; D017124:Conserved Sequence; D042783:Endothelial Cells / Q000378:metabolism; D004730:Endothelium, Vascular / Q000378:metabolism; D018390:Gene Targeting; D007511:Ischemia / Q000628:therapy*; D051379:Mice; D008822:Mice, Transgenic; D011401:Promoter Regions, Genetic; D012045:Regulatory Sequences, Nucleic Acid; D019076:Transgenes; D014945:Wound Healing
D030201:Activin Receptors, Type I; D030301:Activin Receptors, Type II; C498931:Acvrl1 protein, mouse