Loss of Adenomatous Poliposis Coli-α3 Integrin Interaction Promotes Endothelial Apoptosis in Mice and Humans

de Jesus Perez, Vinicio A.; Yuan, Ke; Orcholski, Mark E.; Sawada, Hirofumi; Zhao, Mingming; Li, Caiyun Grace; Tojais, Nancy F.; Nickel, Nils; Rajagopalan, Viswanathan; Spiekerkoetter, Edda; Wang, Lingli; Dutta, Roop; Bernstein, Daniel; Rabinovitch, Marlene

doi:10.1161/CIRCRESAHA.112.267849

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Loss of Adenomatous Poliposis Coli-α3 Integrin Interaction Promotes Endothelial Apoptosis in Mice and Humans

12 7 2012
By de Jesus Perez, Vinicio A. ; Yuan, Ke ; Orcholski, Mark E. ; ...
http://dx.doi.org/10.1161/CIRCRESAHA.112.267849
Source: Circ Res. 111(12)

[PDF-4.12 MB]

English

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Details:

Alternative Title:

Circ Res
Personal Author:

de Jesus Perez, Vinicio A. ; Yuan, Ke ; Orcholski, Mark E. ; Sawada, Hirofumi ; Zhao, Mingming ; ... More +

de Jesus Perez, Vinicio A. ; Yuan, Ke ; Orcholski, Mark E. ; Sawada, Hirofumi ; Zhao, Mingming ; Li, Caiyun Grace ; Tojais, Nancy F. ; Nickel, Nils ; Rajagopalan, Viswanathan ; Spiekerkoetter, Edda ; Wang, Lingli ; Dutta, Roop ; Bernstein, Daniel ; Rabinovitch, Marlene Less -
Description:

Rationale

Pulmonary hypertension (PH) is characterized by progressive elevation in pulmonary pressure and loss of small pulmonary arteries. As bone morphogenetic proteins (BMPs) promote pulmonary angiogenesis by recruiting the Wnt/βcatenin pathway, we proposed that βcatenin activation could reduce loss and/or induce regeneration of small PAs and attenuate PH.

Objective

This study aims to establish the role of β–catenin in protecting the pulmonary endothelium and stimulating compensatory angiogenesis following injury.

Methods and Results

To assess the impact of β-catenin activation on chronic hypoxia-induced PH, we used the adenomatous polyposis coli (ApcMin/+) mouse, where reduced APC causes constitutive β–catenin elevation. Surprisingly, hypoxic ApcMin/+ mice displayed greater PH and small PA loss compared to control C57Bl6J (C57) littermates. Pulmonary artery endothelial cells (PAECs) isolated from ApcMin/+ demonstrated reduced survival and angiogenic responses along with a profound reduction in adhesion to laminin. The mechanism involved failure of APC to interact with the cytoplasmic domain of the α3 integrin, to stabilize focal adhesions and activate integrin-linked kinase (ILK-1) and pAkt. We found that PAECs from lungs of patients with idiopathic PH have reduced APC expression, decreased adhesion to laminin and impaired vascular tube formation. These defects were corrected in the cultured cells by transfection of APC.

Conclusions

We show that APC is integral to PAEC adhesion and survival and is reduced in PAECs from PH patient lungs. The data suggest that decreased APC may be a cause of increased risk or severity of PH in genetically susceptible individuals.
Subjects:

[+]

Adenomatous Poliposis Coli Adenomatous Polyposis Coli Angiogenesis Animals Apoptosis Article Beta Catenin Cell Adhesion Cells, Cultured Cell Survival Endothelial Cells Endothelium, Vascular Female Humans Integrin Alpha3 Integrin Signaling Male Mice Mice, Inbred C57BL Mice, Transgenic Neovascularization, Pathologic Pulmonary Hypertension Respiratory Mucosa Wnt Signaling
Source:

Circ Res. 111(12)
Pubmed ID:

23011394
Pubmed Central ID:

PMC3821702
Document Type:

Journal Article
Funding:

R01 HL074186/HL/NHLBI NIH HHSUnited States/ ; S10 RR027425/RR/NCRR NIH HHSUnited States/ ; S10RR027425/RR/NCRR NIH HHSUnited States/ ; K12 RFA-HL-07-004:CDP/CD/ODCDC CDC HHSUnited States/

R01 HL074186/HL/NHLBI NIH HHSUnited States/ ; S10 RR027425/RR/NCRR NIH HHSUnited States/ ; S10RR027425/RR/NCRR NIH HHSUnited States/ ; K12 RFA-HL-07-004:CDP/CD/ODCDC CDC HHSUnited States/ Less -
Collection(s):

CDC Public Access
Main Document Checksum:

[+]

urn:sha256:e7dc7b79a4cbfa289c21645928e28d9de8345303720652c54d605497712b80cb
Download URL:

https://stacks.cdc.gov/view/cdc/33641/cdc_33641_DS1.pdf
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