Reduced mural cell coverage and impaired vessel integrity after angiogenic stimulation in the Alk1-deficient brain

Authors

Wanqiu Chen, University of California, San Francisco
Yi Guo, University of California, San Francisco
Espen J. Walker, University of California, San Francisco
Fanxia Shen, University of California, San Francisco
Kristine Jun, University of California, San Francisco
S. Paul Oh, University of FloridaFollow
Vincent Degos, University of California, San Francisco
Michael T. Lawton, University of California, San FranciscoFollow
Tarik Tihan, University of California, San Francisco
Dimitrios Davalos, University of California, San Francisco
Katerina Akassoglou, University of California, San Francisco
Jeffrey Nelson, University of California, San Francisco
John Pile-Spellman, Neurological Surgery
Hua Su, University of California, San Francisco
William L. Young, University of California, San Francisco

Document Type

Article

Abstract

Objective-: Vessels in brain arteriovenous malformations are prone to rupture. The underlying pathogenesis is not clear. Hereditary hemorrhagic telangiectasia type 2 patients with activin receptor-like kinase 1 (Alk1) mutation have a higher incidence of brain arteriovenous malformation than the general population. We tested the hypothesis that vascular endothelial growth factor impairs vascular integrity in the Alk1-deficient brain through reduction of mural cell coverage. METHODS AND RESULTS-: Adult Alk1 mice (loxP sites flanking exons 4-6) and wild-type mice were injected with 2×10 PFU adenovious-cre recombinase and 2×10 genome copies of adeno-associated virus-vascular endothelial growth factor to induce focal homozygous Alk1 deletion (in Alk1 mice) and angiogenesis. Brain vessels were analyzed 8 weeks later. Compared with wild-type mice, the Alk1-deficient brain had more fibrin (99±30×10 pixels/mm versus 40±13×10; P=0.001), iron deposition (508±506 pixels/mm versus 6±49; P=0.04), and Iba1 microglia/macrophage infiltration (888±420 Iba1 cells/mm versus 240±104 Iba1; P=0.001) after vascular endothelial growth factor stimulation. In the angiogenic foci, the Alk1-deficient brain had more α-smooth muscle actin negative vessels (52±9% versus 12±7%, P<0.001), fewer vascular-associated pericytes (503±179/mm versus 931±115, P<0.001), and reduced platelet-derived growth factor receptor-β expression. CONCLUSION-: Reduction of mural cell coverage in response to vascular endothelial growth factor stimulation is a potential mechanism for the impairment of vessel wall integrity in hereditary hemorrhagic telangiectasia type 2-associated brain arteriovenous malformation. © 2012 American Heart Association, Inc.

Keywords

activin receptor-like kinase 1, brain arteriovenous malformation, iron deposition, pericyte, platelet-derived growth factor receptor-β

Publication Date

2-1-2013

Publication Title

Arteriosclerosis, Thrombosis, and Vascular Biology

ISSN

10795642

E-ISSN

15244636

Volume

33

Issue

2

First Page

305

Last Page

310

PubMed ID

23241407

Digital Object Identifier (DOI)

10.1161/ATVBAHA.112.300485

Recommended Citation

Chen, Wanqiu; Guo, Yi; Walker, Espen J.; Shen, Fanxia; Jun, Kristine; Oh, S. Paul; Degos, Vincent; Lawton, Michael T.; Tihan, Tarik; Davalos, Dimitrios; Akassoglou, Katerina; Nelson, Jeffrey; Pile-Spellman, John; Su, Hua; and Young, William L., "Reduced mural cell coverage and impaired vessel integrity after angiogenic stimulation in the Alk1-deficient brain" (2013). Translational Neuroscience. 677.
https://scholar.barrowneuro.org/neurobiology/677