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(Chest. 2005;128:564S.)
© 2005 American College of Chest Physicians

The Extracellular Matrix Microenvironment Specifies Pulmonary Endothelial Cell Identity*

Roles of Tenascin-C and RhoA

Lila Sisbarro; Kaori Ihida-Stansbury, PhD; Troy Stevens, PhD; Natalie Bauer; Ivan McMurtry, PhD and Peter Lloyd Jones

* From the Departments of Pediatrics (Ms. Sisbarro, Mr. Ihida-Stansbury, and Mr. Jones) and Medicine (Ms. Bauer and Dr. McMurtry), University of Colorado Health Sciences Center, Denver, CO; and Center for Lung Biology (Dr. Stevens), University of South Alabama, Mobile, AL.

Correspondence to Kaori Ihida-Stansbury, PhD, University of Colorado Health Sciences Center, 4200 E 9th Ave, Room 3432, Box B131, Denver, CO 80262; e-mail: kaori.ihida{at}UCHSC.edu

Endothelial cells (ECs) from the macrovascular (ie, pulmonary artery) and microvascular (ie, pulmonary capillary) beds are phenotypically and functionally distinct. Consistent with this, pulmonary artery ECs (PAECs) within monocrotaline-treated, hypertensive adult rat lungs interact with an extracellular matrix enriched with tenascin-C, whereas pulmonary microvascular ECs (MVECs) do not. This finding suggests that tenascin-C might contribute to EC heterogeneity within the hypertensive lung. To test this, tenascin-C expression was compared in adult rat PAECs and MVECs cultured on tissue culture plastic, chosen to represent an injured tissue microenvironment. Similar to our in vivo findings, tenascin-C expression was significantly greater in cultured PAECs than in MVECs. Since activated focal adhesion kinase (FAK) is required for expression of Prx1, a homeobox gene transcription factor essential for tenascin-C expression, we next examined and found that levels of activated FAK and Prx1 are also higher in tenascin-C–producing PAECs than in MVECs. Furthermore, inhibition of FAK activity not only reduced Prx1 expression in PAECs, but this also resulted in phenotypic change underscored by disruption of cytocortical F-actin. Since tenascin-C modulates F-actin dynamics through suppression of RhoA, (a small guanosine triphosphatase required for F-actin stress fiber formation), we reasoned that RhoA activity and F-actin distribution would differ in PAECs vs MVECs. Indeed, whereas PAECs possessed lower levels of RhoA activity and exhibited cytocortical F-actin, MVECs had higher levels of RhoA activity and displayed prominent F-actin stress fibers. Finally, to determine whether interactions with tenascin-C directly contribute to pulmonary EC heterogeneity, we cultivated tenascin-C–deficient MVECs on exogenous tenascin-C; this treatment suppressed RhoA activity, an event that was associated with loss of F-actin stress fibers in favor of cytocortical F-actin. Collectively, these data indicate that pulmonary EC heterogeneity observed within the hypertensive lung may depend, in part, on the nature of the surrounding extracellular matrix.


   Footnotes
 
Abbreviations: EC = endothelial cell; FAK = focal adhesion kinase; MVEC = microvascular endothelial cell; PAEC = pulmonary artery endothelial cell





This Article
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Right arrow Articles by Sisbarro, L.
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