Endothelial Specificity of ICAM2, Flt-1, and Tie2 Promoters In Vitro and In Vivo
To identify an endothelial cell-specific promoter suitable for vascular-specific targeting, we tested five promoters in vitro--Tie2SE, Tie2LE, ICAM2, Flt-1 and vWF--for promoter activity and specificity in endothelial cells, smooth muscle cells and non-vascular resident cells as well as tissues. These promoters, except for vWF, exhibited good endothelial activity and specificity in vitro. In a syngenic heart transplantation model, the ICAM2 promoter was variably functional in coronary endothelial cells of donor hearts. Thus, the ICAM2, Flt-1, Tie2SE and Tie2LE promoters hold promise for endothelial-specific targeting, but in vitro expression may not predict in vivo expression.
[1] Hajitou A, Pasqualini R, Arap W. Vascular targeting: recent advances
and therapeutic perspectives. Trends Cardiovasc Med. 16 (2006) 80-88.
[2] Schlaeger TM, Bartunkova S, Lawitts JA, Teichmann G, Risau W,
Deutsch U, Sato TN. Uniform vascular-endothelial-cell-specific gene
expression in both embryonic and adult transgenic mice. Proc Natl Acad
Sci U S A 94 (1997) 3058-3063.
[3] Cowan PJ, Shinkel TA, Witort EJ, Barlow H, Pearse MJ, d'Apice AJ.
Targeting gene expression to endothelial cells in transgenic mice using
the human intercellular adhesion molecule 2 promoter. Transplantation
62 (1996) 155-60.
[4] Aird WC, Jahroudi N, Weiler-Guettler H, Rayburn HB, Rosenberg RD.
Human von Willebrand factor gene sequences target expression to a
subpopulation of endothelial cells in transgenic mice. Proc Natl Acad
Sci U S A. 92 (1995) 4567-4571.
[5] Kaoru Morishita, Daniel E. Johnson, and Lewis T. Williams. A novel
promoter for vascular endothelial growth factor receptor (flt-1) that
confers endothelial-specific gene expression. J Biol Chem. 270 (1995)
27948-27953.
[6] Gory S, Vernet M, Laurent M, Dejana E, Dalmon J, Huber P. The
vascular endothelial-cadherin promoter directs endothelial-specific
expression in transgenic mice. Blood 93 (1999) 184-92.
[7] Harats D, Kurihara H, Belloni P, Oakley H, Ziober A, Ackley D, Cain G,
Kurihara Y, Lawn R, Sigal E. Targeting gene expression to the vascular
wall in transgenic mice using the murine preproendothelin-1 promoter. J
Clin Invest. 95 (1995) 1335-44.
[8] Shindo T, Kurihara H, Maemura K, Kurihara Y, Kuwaki T, Izumida T,
Minamino N, Ju KH, Morita H, Oh-hashi Y, Kumada M, Kangawa K,
Nagai R, Yazaki Y. Hypotension and resistance to lipopolysaccharideinduced
shock in transgenic mice overexpressing adrenomedullin in their
vasculature. Circulation 101 (2000) 2309-16.
[9] Nicklin SA, Reynolds PN, Brosnan MJ, White SJ, Curiel DT,
Dominiczak AF, Baker AH. Analysis of cell-specific promoters for viral
gene therapy targeted at the vascular endothelium. Hypertension 38
(2001) 65-70.
[10] Reynolds PN, Nicklin SA, Kaliberova L, Boatman BG, Grizzle WE,
Balyasnikova IV, Baker AH, Danilov SM, Curiel DT. Combined
transductional and transcriptional targeting improves the specificity of
transgene expression in vivo. Nat Biotechnol. 19 (2001) 838-842.
[11] Cowan PJ, Tsang D, Pedic CM, Abbott LR, Shinkel TA, d'Apice AJ,
Pearse MJ. The human ICAM-2 promoter is endothelial cell-specific in
vitro and in vivo and contains critical Sp1 and GATA binding sites. J
Biol Chem. 273 (1998) 11737-11744.
[12] Shinkel TA, Cowan PJ, Barlow H, Aminian A, Romanella M, Lublin
DM, Pearse MJ, d'Apice AJ. Expression and functional analysis of
glycosyl-phosphatidyl inositol-linked CD46 in transgenic mice.
Transplantation 66 (1998) 1401-1406.
[13] Cowan PJ, Shinkel TA, Fisicaro N, Godwin JW, Bernabeu C, Almendro
N, Rius C, Lonie AJ, Nottle MB, Wigley PL, Paizis K, Pearse MJ,
d'Apice AJ. Targeting gene expression to endothelium in transgenic
animals: a comparison of the human ICAM-2, PECAM-1 and endoglin
promoters. Xenotransplantation 10 (2003) 223-31.
[14] Jahroudi N, Schmaier A, Srikanth S, Mahdi F, Lutka FA, Bowser R.
Von Willebrand factor promoter targets the expression of amyloid beta
protein precursor to brain vascular endothelial cells of transgenic mice. J
Alzheimers Dis. 5 (2003) 149-58.
[15] Minami T, Donovan DJ, Tsai JC, Rosenberg RD, Aird WC. Differential
regulation of the von Willebrand factor and Flt-1 promoters in the
endothelium of hypoxanthine phosphoribosyltransferase-targeted mice.
Blood 100 (2002) 4019-4025.
[16] Yu SM, Chen CC, Huang YL, Tsai CW, Lin CH, Huang TF, Teng CM.
Vasorelaxing effect in rat thoracic aorta caused by denudatin B, isolated
from the Chinese herb, magnolia fargesii. Eur J Pharmacol. 187 (1990)
39-47.
[17] Seglen, P. O. Methods Cell Biol. 13 (1976) 29-83.
[18] Ono K, Lindsey ES. Improved technique of heart transplantation in rats.
J Thorac Cardiovasc Surg. 57 (1969) 225.
[1] Hajitou A, Pasqualini R, Arap W. Vascular targeting: recent advances
and therapeutic perspectives. Trends Cardiovasc Med. 16 (2006) 80-88.
[2] Schlaeger TM, Bartunkova S, Lawitts JA, Teichmann G, Risau W,
Deutsch U, Sato TN. Uniform vascular-endothelial-cell-specific gene
expression in both embryonic and adult transgenic mice. Proc Natl Acad
Sci U S A 94 (1997) 3058-3063.
[3] Cowan PJ, Shinkel TA, Witort EJ, Barlow H, Pearse MJ, d'Apice AJ.
Targeting gene expression to endothelial cells in transgenic mice using
the human intercellular adhesion molecule 2 promoter. Transplantation
62 (1996) 155-60.
[4] Aird WC, Jahroudi N, Weiler-Guettler H, Rayburn HB, Rosenberg RD.
Human von Willebrand factor gene sequences target expression to a
subpopulation of endothelial cells in transgenic mice. Proc Natl Acad
Sci U S A. 92 (1995) 4567-4571.
[5] Kaoru Morishita, Daniel E. Johnson, and Lewis T. Williams. A novel
promoter for vascular endothelial growth factor receptor (flt-1) that
confers endothelial-specific gene expression. J Biol Chem. 270 (1995)
27948-27953.
[6] Gory S, Vernet M, Laurent M, Dejana E, Dalmon J, Huber P. The
vascular endothelial-cadherin promoter directs endothelial-specific
expression in transgenic mice. Blood 93 (1999) 184-92.
[7] Harats D, Kurihara H, Belloni P, Oakley H, Ziober A, Ackley D, Cain G,
Kurihara Y, Lawn R, Sigal E. Targeting gene expression to the vascular
wall in transgenic mice using the murine preproendothelin-1 promoter. J
Clin Invest. 95 (1995) 1335-44.
[8] Shindo T, Kurihara H, Maemura K, Kurihara Y, Kuwaki T, Izumida T,
Minamino N, Ju KH, Morita H, Oh-hashi Y, Kumada M, Kangawa K,
Nagai R, Yazaki Y. Hypotension and resistance to lipopolysaccharideinduced
shock in transgenic mice overexpressing adrenomedullin in their
vasculature. Circulation 101 (2000) 2309-16.
[9] Nicklin SA, Reynolds PN, Brosnan MJ, White SJ, Curiel DT,
Dominiczak AF, Baker AH. Analysis of cell-specific promoters for viral
gene therapy targeted at the vascular endothelium. Hypertension 38
(2001) 65-70.
[10] Reynolds PN, Nicklin SA, Kaliberova L, Boatman BG, Grizzle WE,
Balyasnikova IV, Baker AH, Danilov SM, Curiel DT. Combined
transductional and transcriptional targeting improves the specificity of
transgene expression in vivo. Nat Biotechnol. 19 (2001) 838-842.
[11] Cowan PJ, Tsang D, Pedic CM, Abbott LR, Shinkel TA, d'Apice AJ,
Pearse MJ. The human ICAM-2 promoter is endothelial cell-specific in
vitro and in vivo and contains critical Sp1 and GATA binding sites. J
Biol Chem. 273 (1998) 11737-11744.
[12] Shinkel TA, Cowan PJ, Barlow H, Aminian A, Romanella M, Lublin
DM, Pearse MJ, d'Apice AJ. Expression and functional analysis of
glycosyl-phosphatidyl inositol-linked CD46 in transgenic mice.
Transplantation 66 (1998) 1401-1406.
[13] Cowan PJ, Shinkel TA, Fisicaro N, Godwin JW, Bernabeu C, Almendro
N, Rius C, Lonie AJ, Nottle MB, Wigley PL, Paizis K, Pearse MJ,
d'Apice AJ. Targeting gene expression to endothelium in transgenic
animals: a comparison of the human ICAM-2, PECAM-1 and endoglin
promoters. Xenotransplantation 10 (2003) 223-31.
[14] Jahroudi N, Schmaier A, Srikanth S, Mahdi F, Lutka FA, Bowser R.
Von Willebrand factor promoter targets the expression of amyloid beta
protein precursor to brain vascular endothelial cells of transgenic mice. J
Alzheimers Dis. 5 (2003) 149-58.
[15] Minami T, Donovan DJ, Tsai JC, Rosenberg RD, Aird WC. Differential
regulation of the von Willebrand factor and Flt-1 promoters in the
endothelium of hypoxanthine phosphoribosyltransferase-targeted mice.
Blood 100 (2002) 4019-4025.
[16] Yu SM, Chen CC, Huang YL, Tsai CW, Lin CH, Huang TF, Teng CM.
Vasorelaxing effect in rat thoracic aorta caused by denudatin B, isolated
from the Chinese herb, magnolia fargesii. Eur J Pharmacol. 187 (1990)
39-47.
[17] Seglen, P. O. Methods Cell Biol. 13 (1976) 29-83.
[18] Ono K, Lindsey ES. Improved technique of heart transplantation in rats.
J Thorac Cardiovasc Surg. 57 (1969) 225.
@article{"International Journal of Medical, Medicine and Health Sciences:52734", author = "Jing Lei and Yoram Vodovotz and Timothy R. Billiar", title = "Endothelial Specificity of ICAM2, Flt-1, and Tie2 Promoters In Vitro and In Vivo", abstract = "To identify an endothelial cell-specific promoter suitable for vascular-specific targeting, we tested five promoters in vitro--Tie2SE, Tie2LE, ICAM2, Flt-1 and vWF--for promoter activity and specificity in endothelial cells, smooth muscle cells and non-vascular resident cells as well as tissues. These promoters, except for vWF, exhibited good endothelial activity and specificity in vitro. In a syngenic heart transplantation model, the ICAM2 promoter was variably functional in coronary endothelial cells of donor hearts. Thus, the ICAM2, Flt-1, Tie2SE and Tie2LE promoters hold promise for endothelial-specific targeting, but in vitro expression may not predict in vivo expression.
", keywords = "vascular-specific targeting, endothelial cell-specificpromoter, endothelial specificity.", volume = "1", number = "5", pages = "232-5", }
