| First Author | Heberlein KR | Year | 2010 |
| Journal | Circ Res | Volume | 106 |
| Issue | 6 | Pages | 1092-102 |
| PubMed ID | 20133900 | Mgi Jnum | J:170864 |
| Mgi Id | MGI:4947493 | Doi | 10.1161/CIRCRESAHA.109.215723 |
| Citation | Heberlein KR, et al. (2010) Plasminogen activator inhibitor-1 regulates myoendothelial junction formation. Circ Res 106(6):1092-102 |
| abstractText | RATIONALE: Plasminogen activator inhibitor-1 (PAI-1) is a biomarker for several vascular disease states; however, its target of action within the vessel wall is undefined. OBJECTIVE: Determine the ability of PAI-1 to regulate myoendothelial junction (MEJ) formation. METHODS AND RESULTS: MEJs are found throughout the vasculature linking endothelial cells (ECs) and vascular smooth muscle cells. Using a vascular cell coculture we isolated MEJ fractions and performed two-dimensional differential gel electrophoresis. Mass spectrometry identified PAI-1 as being enriched within MEJ fractions, which we confirmed in vivo. In the vascular cell coculture, recombinant PAI-1 added to the EC monolayer significantly increased MEJs. Conversely, addition of a PAI-1 monoclonal antibody to the EC monolayer reduced the number of MEJs. This was also observed in vivo where mice fed a high fat diet had increased PAI-1 and MEJs and the number of MEJs in coronary arterioles of PAI-1(-/-) mice was significantly reduced when compared to C57Bl/6 mice. The presence of MEJs in PAI-1(-/-) coronary arterioles was restored when their hearts were transplanted into and exposed to the circulation of C57Bl/6 mice. Application of biotin-conjugated PAI-1 to the EC monolayer in vitro confirmed the ability of luminal PAI-1 to translocate to the MEJ. Functionally, phenylephrine-induced heterocellular calcium communication in the vascular cell coculture was temporally enhanced when recombinant PAI-1 was present, and prolonged when PAI-1 was absent. CONCLUSION: Our data implicate circulating PAI-1 as a key regulator of MEJ formation and a potential target for pharmacological intervention in diseases with vascular abnormalities (eg, diabetes mellitus). |
