This Article Full Text Full Text (PDF) Data Supplement All Versions of this Article: 93/7/682    most recent 01.RES.0000095246.40391.3Bv1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Seki, T. Articles by Oh, S. P. Search for Related Content PubMed PubMed Citation Articles by Seki, T. Articles by Oh, S. P.

Arterial Endothelium-Specific Activin Receptor-Like Kinase 1 Expression Suggests Its Role in Arterialization and Vascular Remodeling

From the Department of Physiology and Functional Genomics, University of Florida College of Medicine, Gainesville, Fla.

Correspondence to S. Paul Oh, Department of Physiology and Functional Genomics, University of Florida, 1600 SW Archer Rd, D5-36, Gainesville, FL 32610. E-mail ohp{at}phys.med.ufl.edu

Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant vascular disorder characterized by epistaxis, mucocutaneous telangiectases, and arteriovenous malformations (AVM). Two genes are linked to HHT: endoglin (ENG) in HHT1 and activin receptor-like kinase 1 (ACVRL1; ALK1) in HHT2. Although both genes are involved in the transforming growth factor ß signaling pathways, the pathogenetic mechanisms for HHT remain elusive. It was shown that mutations in the Alk1 gene in mice and zebrafish resulted in an embryonic lethal phenotype due to severe dilation of blood vessels. We created a novel null mutant mouse line for Alk1 (Alk1^lacZ) by replacing its exons, including the one that encodes the transmembrane domain, with the ß-galactosidase gene. Using Alk1^lacZ mice, we show that Alk1 is predominantly expressed in developing arterial endothelium. Alk1 expression is greatly diminished in adult arteries, but is induced in preexisting feeding arteries and newly forming arterial vessels during wound healing and tumor angiogenesis. We also show that hemodynamic changes, which require vascular remodeling, may regulate Alk1 expression. Our studies suggest the role of Alk1 signaling in arterialization and remodeling of arteries. Contrary to the current view of HHT as venous disease, our findings suggest that the arterioles rather than the venules are the primary vessels affected by the loss of an Alk1 allele, and that blood vessels with reduction in Alk1 expression may harbor defects in responding to demands for vascular remodeling.

Key Words: activin receptor-like kinase 1 • hereditary hemorrhagic • telangiectasia • angiogenesis • vascular remodeling

This article has been cited by other articles:

				K. Gaengel, G. Genove, A. Armulik, and C. Betsholtz Endothelial-Mural Cell Signaling in Vascular Development and Angiogenesis Arterioscler Thromb Vasc Biol, May 1, 2009; 29(5): 630 - 638. [Abstract] [Full Text] [PDF]

				S. Obi, K. Yamamoto, N. Shimizu, S. Kumagaya, T. Masumura, T. Sokabe, T. Asahara, and J. Ando Fluid shear stress induces arterial differentiation of endothelial progenitor cells J Appl Physiol, January 1, 2009; 106(1): 203 - 211. [Abstract] [Full Text] [PDF]

				A. C. Daly, R. A. Randall, and C. S. Hill Transforming Growth Factor {beta}-Induced Smad1/5 Phosphorylation in Epithelial Cells Is Mediated by Novel Receptor Complexes and Is Essential for Anchorage-Independent Growth Mol. Cell. Biol., November 15, 2008; 28(22): 6889 - 6902. [Abstract] [Full Text] [PDF]

				L. C. Goldie, J. L. Lucitti, M. E. Dickinson, and K. K. Hirschi Cell signaling directing the formation and function of hemogenic endothelium during murine embryogenesis Blood, October 15, 2008; 112(8): 3194 - 3204. [Abstract] [Full Text] [PDF]

				B. Li, W. Yin, X. Hong, Y. Shi, H.-S. Wang, S.-F. Lin, and S.-B. Tang Remodeling Retinal Neovascularization by ALK1 Gene Transfection In Vitro Invest. Ophthalmol. Vis. Sci., October 1, 2008; 49(10): 4553 - 4560. [Abstract] [Full Text] [PDF]

				G. Narazaki, H. Uosaki, M. Teranishi, K. Okita, B. Kim, S. Matsuoka, S. Yamanaka, and J. K. Yamashita Directed and Systematic Differentiation of Cardiovascular Cells From Mouse Induced Pluripotent Stem Cells Circulation, July 29, 2008; 118(5): 498 - 506. [Abstract] [Full Text] [PDF]

				S. O. Park, Y. J. Lee, T. Seki, K.-H. Hong, N. Fliess, Z. Jiang, A. Park, X. Wu, V. Kaartinen, B. L. Roman, et al. ALK5- and TGFBR2-independent role of ALK1 in the pathogenesis of hereditary hemorrhagic telangiectasia type 2 Blood, January 15, 2008; 111(2): 633 - 642. [Abstract] [Full Text] [PDF]

				Y. Lan, B. Liu, H. Yao, F. Li, T. Weng, G. Yang, W. Li, X. Cheng, N. Mao, and X. Yang Essential Role of Endothelial Smad4 in Vascular Remodeling and Integrity Mol. Cell. Biol., November 1, 2007; 27(21): 7683 - 7692. [Abstract] [Full Text] [PDF]

				M. Scharpfenecker, M. van Dinther, Z. Liu, R.L. van Bezooijen, Q. Zhao, L. Pukac, C. W. G. M. Lowik, and P. ten Dijke BMP-9 signals via ALK1 and inhibits bFGF-induced endothelial cell proliferation and VEGF-stimulated angiogenesis J. Cell Sci., March 15, 2007; 120(6): 964 - 972. [Abstract] [Full Text] [PDF]

				F. Lanner, M. Sohl, and F. Farnebo Functional Arterial and Venous Fate Is Determined by Graded VEGF Signaling and Notch Status During Embryonic Stem Cell Differentiation Arterioscler Thromb Vasc Biol, March 1, 2007; 27(3): 487 - 493. [Abstract] [Full Text] [PDF]

				W. C. Aird Phenotypic Heterogeneity of the Endothelium: II. Representative Vascular Beds Circ. Res., February 2, 2007; 100(2): 174 - 190. [Abstract] [Full Text] [PDF]

				A. Ishimura, J. K. Ng, M. Taira, S. G. Young, and S.-I. Osada Man1, an inner nuclear membrane protein, regulates vascular remodeling by modulating transforming growth factor {beta} signaling Development, October 1, 2006; 133(19): 3919 - 3928. [Abstract] [Full Text] [PDF]

				C. Varon, F. Tatin, V. Moreau, E. Van Obberghen-Schilling, S. Fernandez-Sauze, E. Reuzeau, I. Kramer, and E. Genot Transforming Growth Factor {beta} Induces Rosettes of Podosomes in Primary Aortic Endothelial Cells. Mol. Cell. Biol., May 1, 2006; 26(9): 3582 - 3594. [Abstract] [Full Text] [PDF]

				J. L. Jadrich, M. B. O'Connor, and E. Coucouvanis The TGF{beta} activated kinase TAK1 regulates vascular development in vivo. Development, April 1, 2006; 133(8): 1529 - 1541. [Abstract] [Full Text] [PDF]

				S A Abdalla and M Letarte Hereditary haemorrhagic telangiectasia: current views on genetics and mechanisms of disease J. Med. Genet., February 1, 2006; 43(2): 97 - 110. [Abstract] [Full Text] [PDF]

				T. Stevens Molecular and Cellular Determinants of Lung Endothelial Cell Heterogeneity Chest, December 1, 2005; 128(6_suppl): 558S - 564S. [Abstract] [Full Text] [PDF]

				A. Fernandez-L, F. Sanz-Rodriguez, R. Zarrabeitia, A. Perez-Molino, R. P. Hebbel, J. Nguyen, C. Bernabeu, and L.-M. Botella Blood outgrowth endothelial cells from Hereditary Haemorrhagic Telangiectasia patients reveal abnormalities compatible with vascular lesions Cardiovasc Res, November 1, 2005; 68(2): 235 - 248. [Abstract] [Full Text] [PDF]

				M. Whitman and L. Raftery TGF{beta} signaling at the summit Development, October 1, 2005; 132(19): 4205 - 4210. [Abstract] [Full Text] [PDF]

				J. G. R. De Mey, P. M. Schiffers, R. H. P. Hilgers, and M. M. W. Sanders Toward functional genomics of flow-induced outward remodeling of resistance arteries Am J Physiol Heart Circ Physiol, March 1, 2005; 288(3): H1022 - H1027. [Abstract] [Full Text] [PDF]

				T. Seki, K.-H. Hong, J. Yun, S.-J. Kim, and S. P. Oh Isolation of a Regulatory Region of Activin Receptor-Like Kinase 1 Gene Sufficient for Arterial Endothelium-Specific Expression Circ. Res., April 30, 2004; 94(8): e72 - e77. [Abstract] [Full Text] [PDF]