The role of endothelial MERTK during the inflammatory response in lungs.

As a key homeostasis regulator in mammals, the MERTK receptor tyrosine kinase is crucial for efferocytosis, a process that requires remodeling of the cell membrane and adjacent actin cytoskeleton. Membrane and cytoskeletal reorganization also occur in endothelial cells during inflammation, particularly during neutrophil transendothelial migration (TEM) and during changes in permeability. However, MERTK's function in endothelial cells remains unclear.

The matrikine N-α-PGP couples extracellular matrix fragmentation to endothelial permeability.

The compartmentalization and transport of proteins and solutes across the endothelium is a critical biologic function altered during inflammation and disease, leading to pathology in multiple disorders. The impact of tissue damage and subsequent extracellular matrix (ECM) fragmentation in regulating this process is unknown. We demonstrate that the collagen-derived matrikine acetylated proline-glycine-proline (N-α-PGP) serves as a critical regulator of endothelial permeability.

JNK2 promotes endothelial cell alignment under flow.

Endothelial cells in straight, unbranched segments of arteries elongate and align in the direction of flow, a feature which is highly correlated with reduced atherosclerosis in these regions. The mitogen-activated protein kinase c-Jun N-terminal kinase (JNK) is activated by flow and is linked to inflammatory gene expression and apoptosis. We previously showed that JNK activation by flow is mediated by integrins and is observed in cells plated on fibronectin but not on collagen or basement membrane proteins.

Focal adhesion kinase modulates activation of NF-kappaB by flow in endothelial cells.

Atherogenesis involves activation of NF-kappaB in endothelial cells by fluid shear stress. Because this pathway involves integrins, we investigated the involvement of focal adhesion kinase (FAK). We found that FAK was not required for flow-stimulated translocation of the p65 NF-kappaB subunit to the nucleus but was essential for phosphorylation of p65 on serine 536 and induction of ICAM-1, an NF-kappaB-dependent gene.

The subendothelial extracellular matrix modulates JNK activation by flow.

Atherosclerosis begins as local inflammation of artery walls at sites of disturbed flow. JNK (c-Jun NH(2)-terminal kinase) is thought to be among the major regulators of flow-dependent inflammatory gene expression in endothelial cells in atherosclerosis. We now show that JNK activation by both onset of laminar flow and long-term oscillatory flow is matrix-specific, with enhanced activation on fibronectin compared to basement membrane protein or collagen.

Mechanotransduction in vascular physiology and atherogenesis.

Forces that are associated with blood flow are major determinants of vascular morphogenesis and physiology. Blood flow is crucial for blood vessel development during embryogenesis and for regulation of vessel diameter in adult life. It is also a key factor in atherosclerosis, which, despite the systemic nature of major risk factors, occurs mainly in regions of arteries that experience disturbances in fluid flow.

The role of cellular adaptation to mechanical forces in atherosclerosis.

Atherosclerosis is a chronic inflammatory disease that originates at regions of arteries exposed to disturbances in fluid flow and results in progressive plaque formation in those areas. Recent work on cellular responses to flow has identified potential mechanosensors and pathways that may influence disease progression. These results led us to hypothesize that the same mechanisms that mediate adaptive responses in the vasculature become maladaptive at sites of disturbed flow.

p21-activated kinase signaling regulates oxidant-dependent NF-kappa B activation by flow.

Disturbed blood flow induces inflammatory gene expression in endothelial cells, which promotes atherosclerosis. Flow stimulates the proinflammatory transcription factor nuclear factor (NF)-kappaB through integrin- and Rac-dependent production of reactive oxygen species (ROS). Previous work demonstrated that NF-kappaB activation by flow is matrix-specific, occurring in cells on fibronectin but not collagen.

Can circulatory fetal DNA be used to study placentation at high altitude?

Pregnancy at high altitude (>2700 m) is associated with higher rates of fetal growth restriction and preeclampsia as well as alterations in placentation, including increased villous vascularization and reduced remodeling of maternal spiral arteries. Because circulatory fetal DNA concentrations were shown to be enhanced in pregnancies affected by preeclampsia, we investigated whether similar elevations are also apparent in pregnancies at high altitude by examining ethnic Tibetans and recent migrant Han Chinese residents in Lhasa (altitude 3650 m) as well as Han Chinese residents in Guangzhou (altitude 7 m). Our data from this preliminary study (n = 10/study group) indicate that circulatory fetal DNA levels were significantly higher in the unremarkable pregnancies of Han women who moved to Tibet when compared to Han women at sea level.

Specific beta1 integrin site selectively regulates Akt/protein kinase B signaling via local activation of protein phosphatase 2A.

Integrin transmembrane receptors generate multiple signals, but how they mediate specific signaling is not clear. Here we test the hypothesis that particular sequences along the beta(1) integrin cytoplasmic domain may exist that are intimately related to specific integrin-mediated signaling pathways. Using systematic alanine mutagenesis of amino acids conserved between different beta integrin cytoplasmic domains, we identified the tryptophan residue at position 775 of human beta(1) integrin as specific and necessary for integrin-mediated protein kinase B/Akt survival signaling.