Go to JCI Insight
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Alerts
  • Advertising
  • Job board
  • Subscribe
  • Contact
  • Current issue
  • Past issues
  • By specialty
    • COVID-19
    • Cardiology
    • Gastroenterology
    • Immunology
    • Metabolism
    • Nephrology
    • Neuroscience
    • Oncology
    • Pulmonology
    • Vascular biology
    • All ...
  • Videos
    • Conversations with Giants in Medicine
    • Author's Takes
  • Reviews
    • View all reviews ...
    • Next-Generation Sequencing in Medicine (Upcoming)
    • New Therapeutic Targets in Cardiovascular Diseases (Mar 2022)
    • Immunometabolism (Jan 2022)
    • Circadian Rhythm (Oct 2021)
    • Gut-Brain Axis (Jul 2021)
    • Tumor Microenvironment (Mar 2021)
    • 100th Anniversary of Insulin's Discovery (Jan 2021)
    • View all review series ...
  • Viewpoint
  • Collections
    • In-Press Preview
    • Commentaries
    • Concise Communication
    • Editorials
    • Viewpoint
    • Top read articles
  • Clinical Medicine
  • JCI This Month
    • Current issue
    • Past issues

  • Current issue
  • Past issues
  • Specialties
  • Reviews
  • Review series
  • Conversations with Giants in Medicine
  • Author's Takes
  • In-Press Preview
  • Commentaries
  • Concise Communication
  • Editorials
  • Viewpoint
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Alerts
  • Advertising
  • Job board
  • Subscribe
  • Contact

Vascular biology

  • 264 Articles
  • 8 Posts
  • ← Previous
  • 1
  • 2
  • …
  • 23
  • 24
  • 25
  • 26
  • 27
  • Next →
Reversal of experimental pulmonary hypertension by PDGF inhibition
Ralph Theo Schermuly, … , Werner Seeger, Friedrich Grimminger
Ralph Theo Schermuly, … , Werner Seeger, Friedrich Grimminger
Published October 3, 2005
Citation Information: J Clin Invest. 2005;115(10):2811-2821. https://doi.org/10.1172/JCI24838.
View: Text | PDF

Reversal of experimental pulmonary hypertension by PDGF inhibition

  • Text
  • PDF
Abstract

Progression of pulmonary hypertension is associated with increased proliferation and migration of pulmonary vascular smooth muscle cells. PDGF is a potent mitogen and involved in this process. We now report that the PDGF receptor antagonist STI571 (imatinib) reversed advanced pulmonary vascular disease in 2 animal models of pulmonary hypertension. In rats with monocrotaline-induced pulmonary hypertension, therapy with daily administration of STI571 was started 28 days after induction of the disease. A 2-week treatment resulted in 100% survival, compared with only 50% in sham-treated rats. The changes in RV pressure, measured continuously by telemetry, and right heart hypertrophy were reversed to near-normal levels. STI571 prevented phosphorylation of the PDGF receptor and suppressed activation of downstream signaling pathways. Similar results were obtained in chronically hypoxic mice, which were treated with STI571 after full establishment of pulmonary hypertension. Moreover, expression of the PDGF receptor was found to be significantly increased in lung tissue from pulmonary arterial hypertension patients compared with healthy donor lung tissue. We conclude that STI571 reverses vascular remodeling and cor pulmonale in severe experimental pulmonary hypertension regardless of the initiating stimulus. This regimen offers a unique novel approach for antiremodeling therapy in progressed pulmonary hypertension.

Authors

Ralph Theo Schermuly, Eva Dony, Hossein Ardeschir Ghofrani, Soni Pullamsetti, Rajkumar Savai, Markus Roth, Akylbek Sydykov, Ying Ju Lai, Norbert Weissmann, Werner Seeger, Friedrich Grimminger

×

The cytoskeletal protein ezrin regulates EC proliferation and angiogenesis via TNF-α-induced transcriptional repression of cyclin A
Raj Kishore, … , David Goukassain, Douglas W. Losordo
Raj Kishore, … , David Goukassain, Douglas W. Losordo
Published October 1, 2005
Citation Information: J Clin Invest. 2005;115(10):2955-2955. https://doi.org/10.1172/JCI22849C1.
View: Text | PDF | Amended Article

The cytoskeletal protein ezrin regulates EC proliferation and angiogenesis via TNF-α-induced transcriptional repression of cyclin A

  • Text
  • PDF
Abstract

Authors

Raj Kishore, Gangjian Qin, Corinne Luedemann, Evelyn Bord, Allison Hanley, Marcy Silver, Mary Gavin, Young-sup Yoon, David Goukassain, Douglas W. Losordo

×

Ets-1 is a critical regulator of Ang II-mediated vascular inflammation and remodeling
Yumei Zhan, … , I-Cheng Ho, Peter Oettgen
Yumei Zhan, … , I-Cheng Ho, Peter Oettgen
Published September 1, 2005
Citation Information: J Clin Invest. 2005;115(9):2508-2516. https://doi.org/10.1172/JCI24403.
View: Text | PDF

Ets-1 is a critical regulator of Ang II-mediated vascular inflammation and remodeling

  • Text
  • PDF
Abstract

Ang II is a central mediator of vascular inflammation and remodeling. The transcription factor Ets-1 is rapidly induced in vascular smooth muscle and endothelial cells of the mouse thoracic aorta in response to systemic Ang II infusion. Arterial wall thickening, perivascular fibrosis, and cardiac hypertrophy are significantly diminished in Ets1–/– mice compared with control mice in response to Ang II. The induction of 2 known targets of Ets-1, cyclin-dependent kinase inhibitor p21CIP and plasminogen activator inhibitor–1 (PAI-1), by Ang II is markedly blunted in the aorta of Ets1–/– mice compared with wild-type controls. Expression of p21CIP in VSMCs leads to cellular hypertrophy, whereas expression of p21CIP in endothelial cells is associated with cell cycle arrest, apoptosis, and endothelial dysfunction. PAI-1 promotes the development of perivascular fibrosis. We have identified monocyte chemoattractant protein–1 (MCP-1) as a novel target for Ets-1. Expression of MCP-1 is similarly reduced in Ets1–/– mice compared with control mice in response to Ang II, which results in significantly diminished recruitment of T cells and macrophages to the vessel wall. In summary, our results support a critical role for Ets-1 as a transcriptional mediator of vascular inflammation and remodeling in response to Ang II.

Authors

Yumei Zhan, Courtney Brown, Elizabeth Maynard, Aleksandra Anshelevich, Weihua Ni, I-Cheng Ho, Peter Oettgen

×

Akt1/protein kinase Bα is critical for ischemic and VEGF-mediated angiogenesis
Eric Ackah, … , Kenneth Walsh, William C. Sessa
Eric Ackah, … , Kenneth Walsh, William C. Sessa
Published August 1, 2005
Citation Information: J Clin Invest. 2005;115(8):2119-2127. https://doi.org/10.1172/JCI24726.
View: Text | PDF

Akt1/protein kinase Bα is critical for ischemic and VEGF-mediated angiogenesis

  • Text
  • PDF
Abstract

Akt, or protein kinase B, is a multifunctional serine-threonine protein kinase implicated in a diverse range of cellular functions including cell metabolism, survival, migration, and gene expression. However, the in vivo roles and effectors of individual Akt isoforms in signaling are not explicitly clear. Here we show that the genetic loss of Akt1, but not Akt2, in mice results in defective ischemia and VEGF-induced angiogenesis as well as severe peripheral vascular disease. Akt1 knockout (Akt1–/–) mice also have reduced endothelial progenitor cell (EPC) mobilization in response to ischemia, and reintroduction of WT EPCs, but not EPCs isolated from Akt1–/– mice, into WT mice improves limb blood flow after ischemia. Mechanistically, the loss of Akt1 reduces the basal phosphorylation of several Akt substrates, the migration of fibroblasts and ECs, and NO release. Reconstitution of Akt1–/– ECs with Akt1 rescues the defects in substrate phosphorylation, cell migration, and NO release. Thus, the Akt1 isoform exerts an essential role in blood flow control, cellular migration, and NO synthesis during postnatal angiogenesis.

Authors

Eric Ackah, Jun Yu, Stefan Zoellner, Yasuko Iwakiri, Carsten Skurk, Rei Shibata, Noriyuki Ouchi, Rachael M. Easton, Gennaro Galasso, Morris J. Birnbaum, Kenneth Walsh, William C. Sessa

×

The cytoskeletal protein ezrin regulates EC proliferation and angiogenesis via TNF-α–induced transcriptional repression of cyclin A
Raj Kishore, … , David Goukassain, Douglas W. Losordo
Raj Kishore, … , David Goukassain, Douglas W. Losordo
Published July 1, 2005
Citation Information: J Clin Invest. 2005;115(7):1785-1796. https://doi.org/10.1172/JCI22849.
View: Text | PDF | Corrigendum | Erratum

The cytoskeletal protein ezrin regulates EC proliferation and angiogenesis via TNF-α–induced transcriptional repression of cyclin A

  • Text
  • PDF
Abstract

TNF-α modulates EC proliferation and thereby plays a central role in new blood vessel formation in physiologic and pathologic circumstances. TNF-α is known to downregulate cyclin A, a key cell cycle regulatory protein, but little else is known about how TNF-α modulates EC cell cycle and angiogenesis. Using primary ECs, we show that ezrin, previously considered to act primarily as a cytoskeletal protein and in cytoplasmic signaling, is a TNF-α–induced transcriptional repressor. TNF-α exposure leads to Rho kinase–mediated phosphorylation of ezrin, which translocates to the nucleus and binds to cell cycle homology region repressor elements within the cyclin A promoter. Overexpression of dominant-negative ezrin blocks TNF-α–induced modulation of ezrin function and rescues cyclin A expression and EC proliferation. In vivo, blockade of ezrin leads to enhanced transplanted EC proliferation and angiogenesis in a mouse hind limb ischemia model. These observations suggest that TNF-α regulates angiogenesis via Rho kinase induction of a transcriptional repressor function of the cytoskeletal protein ezrin and that ezrin may represent a suitable therapeutic target for processes dependent on EC proliferation.

Authors

Raj Kishore, Gangjian Qin, Corinne Luedemann, Evelyn Bord, Allison Hanley, Marcy Silver, Mary Gavin, David Goukassain, Douglas W. Losordo

×

Requirement for sphingosine 1–phosphate receptor-1 in tumor angiogenesis demonstrated by in vivo RNA interference
Sung-Suk Chae, … , Henry Furneaux, Timothy Hla
Sung-Suk Chae, … , Henry Furneaux, Timothy Hla
Published October 15, 2004
Citation Information: J Clin Invest. 2004;114(8):1082-1089. https://doi.org/10.1172/JCI22716.
View: Text | PDF

Requirement for sphingosine 1–phosphate receptor-1 in tumor angiogenesis demonstrated by in vivo RNA interference

  • Text
  • PDF
Abstract

Angiogenesis, or new blood vessel formation, is critical for the growth and spread of tumors. Multiple phases of this process, namely, migration, proliferation, morphogenesis, and vascular stabilization, are needed for optimal tumor growth beyond a diffusion-limited size. The sphingosine 1–phosphate (S1P) receptor-1 (S1P1) is required for stabilization of nascent blood vessels during embryonic development. Here we show that S1P1 expression is strongly induced in tumor vessels. We developed a multiplex RNA interference technique to downregulate S1P1 in mice. The small interfering RNA (siRNA) for S1P1 specifically silenced the cognate transcript in endothelial cells and inhibited endothelial cell migration in vitro and the growth of neovessels into subcutaneous implants of Matrigel in vivo. Local injection of S1P1 siRNA, but not a negative control siRNA, into established tumors inhibited the expression of S1P1 polypeptide on neovessels while concomitantly suppressing vascular stabilization and angiogenesis, which resulted in dramatic suppression of tumor growth in vivo. These data suggest that S1P1 is a critical component of the tumor angiogenic response and argue for the utility of siRNA technology in antiangiogenic therapeutics.

Authors

Sung-Suk Chae, Ji-Hye Paik, Henry Furneaux, Timothy Hla

×

Effect of fetal hemoglobin on microvascular regulation in sickle transgenic-knockout mice
Dhananjay K. Kaul, … , Ronald L. Nagel, Mary E. Fabry
Dhananjay K. Kaul, … , Ronald L. Nagel, Mary E. Fabry
Published October 15, 2004
Citation Information: J Clin Invest. 2004;114(8):1136-1145. https://doi.org/10.1172/JCI21633.
View: Text | PDF

Effect of fetal hemoglobin on microvascular regulation in sickle transgenic-knockout mice

  • Text
  • PDF
Abstract

In sickle cell disease, intravascular sickling and attendant flow abnormalities underlie the chronic inflammation and vascular endothelial abnormalities. However, the relationship between sickling and vascular tone is not well understood. We hypothesized that sickling-induced vaso-occlusive events and attendant oxidative stress will affect microvascular regulatory mechanisms. In the present studies, we have examined whether microvascular abnormalities expressed in sickle transgenic-knockout Berkeley (BERK) mice (which express exclusively human α- and βS-globins with <1% γ-globin levels) are amenable to correction with increased levels of antisickling fetal hemoglobin (HbF). In BERK mice, sickling, increased oxidative stress, and hemolytic anemia are accompanied by vasodilation, compensatory increases in eNOS and COX-2, and attenuated vascular responses to NO-mediated vasoactive stimuli and norepinephrine. The hypotension and vasodilation (required for adequate oxygen delivery in the face of chronic anemia) are mediated by non-NO vasodilators (i.e., prostacyclin) as evidenced by induction of COX-2. In BERK mice, the resistance to NO-mediated vasodilators is associated with increased oxidative stress and hemolytic rate, and in BERK + γ mice (expressing 20% HbF), an improved response to these stimuli is associated with reduced oxidative stress and hemolytic rate. Furthermore, BERK + γ mice show normalization of vessel diameters, and eNOS and COX-2 expression. These results demonstrate a strong relationship between sickling and microvascular function in sickle cell disease.

Authors

Dhananjay K. Kaul, Xiao-du Liu, Hee-Yoon Chang, Ronald L. Nagel, Mary E. Fabry

×

Increased DC trafficking to lymph nodes and contact hypersensitivity in junctional adhesion molecule-A–deficient mice
Maria Rosaria Cera, … , Alberto Mantovani, Elisabetta Dejana
Maria Rosaria Cera, … , Alberto Mantovani, Elisabetta Dejana
Published September 1, 2004
Citation Information: J Clin Invest. 2004;114(5):729-738. https://doi.org/10.1172/JCI21231.
View: Text | PDF

Increased DC trafficking to lymph nodes and contact hypersensitivity in junctional adhesion molecule-A–deficient mice

  • Text
  • PDF
Abstract

Junctional adhesion molecule-A (JAM-A) is a transmembrane adhesive protein expressed at endothelial junctions and in leukocytes. In the present work, we found that DCs also express JAM-A. To evaluate the biological relevance of this observation, Jam-A–/– mice were generated and the functional behavior of DCs in vitro and in vivo was studied. In vitro, Jam-A–/– DCs showed a selective increase in random motility and in the capacity to transmigrate across lymphatic endothelial cells. In vivo, Jam-A–/– mice showed enhanced DC migration to lymph nodes, which was not observed in mice with endothelium-restricted deficiency of the protein. Furthermore, increased DC migration to lymph nodes was associated with enhanced contact hypersensitivity (CHS). Adoptive transfer experiments showed that JAM-A–deficient DCs elicited increased CHS in Jam-A+/+ mice, further supporting the concept of a DC-specific effect. Thus, we identified here a novel, non-redundant role of JAM-A in controlling DC motility, trafficking to lymph nodes, and activation of specific immunity.

Authors

Maria Rosaria Cera, Annalisa Del Prete, Annunciata Vecchi, Monica Corada, Ines Martin-Padura, Toshiyuki Motoike, Paolo Tonetti, Gianfranco Bazzoni, William Vermi, Francesca Gentili, Sergio Bernasconi, Thomas N. Sato, Alberto Mantovani, Elisabetta Dejana

×

Integrin engagement regulates monocyte differentiation through the forkhead transcription factor Foxp1
Can Shi, … , Mukesh K. Jain, Daniel I. Simon
Can Shi, … , Mukesh K. Jain, Daniel I. Simon
Published August 1, 2004
Citation Information: J Clin Invest. 2004;114(3):408-418. https://doi.org/10.1172/JCI21100.
View: Text | PDF

Integrin engagement regulates monocyte differentiation through the forkhead transcription factor Foxp1

  • Text
  • PDF
Abstract

The precise signals responsible for differentiation of blood-borne monocytes into tissue macrophages are incompletely defined. “Outside-in” signaling by integrins has been implicated in modulation of gene expression that affects cellular differentiation. Herein, using differential display PCR, we have cloned an 85-kDa forkhead transcription factor (termed Mac-1–regulated forkhead [MFH] and found subsequently to be identical to Foxp1) that is downregulated in β2-integrin Mac-1–clustered compared with Mac-1–nonclustered monocytic THP-1 cells. MFH/Foxp1 is expressed in untreated HL60 cells, and its expression was markedly reduced during phorbol ester–induced monocyte differentiation, but not retinoic acid–induced granulocyte differentiation. Overexpression of MFH/Foxp1 markedly attenuated phorbol ester–induced expression of c-fms, which encodes the M-CSF receptor and is obligatory for macrophage differentiation. This was accompanied by decreased CD11b expression, cell adhesiveness, and phagocytosis. Using electromobility shift and reporter assays, we have established that MFH/Foxp1 binds to previously uncharacterized sites within the c-fms promoter and functions as a transcriptional repressor. Deficiency of Mac-1 is associated with altered regulation of MFH/Foxp1 and monocyte maturation in vivo. Taken together, these observations suggest that Mac-1 engagement orchestrates monocyte-differentiation signals by regulating the expression of the forkhead transcription repressor MFH/Foxp1. This represents a new pathway for integrin-dependent modulation of gene expression and control of cellular differentiation.

Authors

Can Shi, Xiaobin Zhang, Zhiping Chen, Karina Sulaiman, Mark W. Feinberg, Christie M. Ballantyne, Mukesh K. Jain, Daniel I. Simon

×

Targeted deletion of BMK1/ERK5 in adult mice perturbs vascular integrity and leads to endothelial failure
Masaaki Hayashi, … , Richard J. Ulevitch, Jiing-Dwan Lee
Masaaki Hayashi, … , Richard J. Ulevitch, Jiing-Dwan Lee
Published April 15, 2004
Citation Information: J Clin Invest. 2004;113(8):1138-1148. https://doi.org/10.1172/JCI19890.
View: Text | PDF

Targeted deletion of BMK1/ERK5 in adult mice perturbs vascular integrity and leads to endothelial failure

  • Text
  • PDF
Abstract

Big mitogen-activated protein kinase 1 (BMK1), also known as ERK5, is a member of the MAPK family. Genetic ablation of BMK1 in mice leads to embryonic lethality, precluding the exploration of pathophysiological roles of BMK1 in adult mice. We generated a BMK1 conditional mutation in mice in which disruption of the BMK1 gene is under the control of the inducible Mx1-Cre transgene. Ablation of BMK1 in adult mice led to lethality within 2–4 weeks after the induction of Cre recombinase. Physiological analysis showed that the blood vessels became abnormally leaky after deletion of the BMK1 gene. Histological analysis revealed that, after BMK1 ablation, hemorrhages occurred in multiple organs in which endothelial cells lining the blood vessels became round, irregularly aligned, and, eventually, apoptotic. In vitro removal of BMK1 protein also led to the death of endothelial cells partially due to the deregulation of transcriptional factor MEF2C, which is a direct substrate of BMK1. Additionally, endothelial-specific BMK1-KO leads to cardiovascular defects identical to that of global BMK1-KO mutants, whereas, surprisingly, mice lacking BMK1 in cardiomyocytes developed to term without any apparent defects. Taken together, the data provide direct genetic evidence that the BMK1 pathway is critical for endothelial function and for maintaining blood vessel integrity.

Authors

Masaaki Hayashi, Sung-Woo Kim, Kyoko Imanaka-Yoshida, Toshimichi Yoshida, E. Dale Abel, Brian Eliceiri, Young Yang, Richard J. Ulevitch, Jiing-Dwan Lee

×
  • ← Previous
  • 1
  • 2
  • …
  • 23
  • 24
  • 25
  • 26
  • 27
  • Next →
MiR-33 fine-tunes atherosclerotic plaque inflammation
Mireille Ouimet, Hasini Ediriweera, and colleagues show that miR-33 controls the macrophage inflammatory program and promotes atherosclerotic plaque development…
Published October 26, 2015
Scientific Show StopperVascular biology

Contracting lacteals send lipids down the drain
Kibaek Choe, Jeon Yeob Jang, Intae Park and colleagues visualize lipid drainage through lacteals using intravital, video-rate microscopy…
Published October 5, 2015
Scientific Show StopperVascular biology

FOXC2 keeps lymphatic vessels leak-proof
Amélie Sabine and colleagues demonstrate that disturbed flow in lymphatic vasculature induces expression of the transcription factor FOXC2, which is essential for maintaining normal endothelial cell morphology and vessel integrity…
Published September 21, 2015
Scientific Show StopperVascular biology

Venous malformation model provides therapeutic insight
Elisa Boscolo and colleagues develop a murine model of venous malformation and demonstrate that rapamycin improves clinical symptoms of in this model and in patients…
Published August 10, 2015
Scientific Show StopperVascular biology

Lymphatic valves grow with the flow
Daniel Sweet and colleagues reveal that lymph flow is essential for lymphatic vessel maturation…
Published July 27, 2015
Scientific Show StopperVascular biology

GATA2 serves as a lymphatic rheostat
Jan Kazenwadel, Kelly Betterman, and colleagues reveal that the transcription factor GATA2 is essential for lymphatic valve development and maintenance…
Published July 27, 2015
Scientific Show StopperVascular biology

Factoring in factor XII in hereditary angioedema III
Jenny Björkqvist and colleagues elucidate the mechanism by which hereditary angioedema III-associated factor XII promotes vascular leakage…
Published July 20, 2015
Scientific Show StopperVascular biology

Regional regulation of atherosclerosis
Yogendra Kanthi, Matthew Hyman, and colleagues reveal that CD39 is regulated by blood flow and is protective against atherosclerosis…
Published June 29, 2015
Scientific Show StopperVascular biology
Advertisement

Copyright © 2022 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

Sign up for email alerts