uu.seUppsala University Publications
Change search
Link to record
Permanent link

Direct link
BETA
Hofmann, Jennifer J.
Alternative names
Publications (4 of 4) Show all publications
Mäe, M. A., Li, T., Bertuzzi, G., Raschperger, E., Vanlandewijck, M., He, L., . . . Genove, G. (2018). Prolonged systemic hyperglycemia does not cause pericyte loss and permeability at the mouse blood-brain barrier. Scientific Reports, 8, Article ID 17462.
Open this publication in new window or tab >>Prolonged systemic hyperglycemia does not cause pericyte loss and permeability at the mouse blood-brain barrier
Show others...
2018 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 8, article id 17462Article in journal (Refereed) Published
Abstract [en]

Diabetes mellitus is associated with cognitive impairment and various central nervous system pathologies such as stroke, vascular dementia, or Alzheimer's disease. The exact pathophysiology of these conditions is poorly understood. Recent reports suggest that hyperglycemia causes cerebral microcirculation pathology and blood-brain barrier (BBB) dysfunction and leakage. The majority of these reports, however, are based on methods including in vitro BBB modeling or streptozotocininduced diabetes in rodents, opening questions regarding the translation of the in vitro findings to the in vivo situation, and possible direct effects of streptozotocin on the brain vasculature. Here we used a genetic mouse model of hyperglycemia (Ins2(AKITA)) to address whether prolonged systemic hyperglycemia induces BBB dysfunction and leakage. We applied a variety of methodologies to carefully evaluate BBB function and cellular integrity in vivo, including the quantification and visualization of specific tracers and evaluation of transcriptional and morphological changes in the BBB and its supporting cellular components. These experiments did neither reveal altered BBB permeability nor morphological changes of the brain vasculature in hyperglycemic mice. We conclude that prolonged hyperglycemia does not lead to BBB dysfunction, and thus the cognitive impairment observed in diabetes may have other causes.

Place, publisher, year, edition, pages
NATURE PUBLISHING GROUP, 2018
National Category
Neurosciences
Identifiers
urn:nbn:se:uu:diva-372388 (URN)10.1038/s41598-018-35576-0 (DOI)000451619100004 ()30498224 (PubMedID)
Funder
Swedish Research Council, 2015-00550EU, European Research Council, AdG294556Knut and Alice Wallenberg Foundation, 2015.0030Swedish Cancer Society, CAN-2016-0777Swedish Cancer Society, 150735
Available from: 2019-01-07 Created: 2019-01-07 Last updated: 2019-01-07Bibliographically approved
Niaudet, C., Hofmann, J. J., Mae, M. A., Jung, B., Gängel, K., Vanlandewijck, M., . . . Betsholtz, C. (2015). Gpr116 Receptor Regulates Distinctive Functions in Pneumocytes and Vascular Endothelium. PLoS ONE, 10(9), Article ID e0137949.
Open this publication in new window or tab >>Gpr116 Receptor Regulates Distinctive Functions in Pneumocytes and Vascular Endothelium
Show others...
2015 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 10, no 9, article id e0137949Article in journal (Refereed) Published
Abstract [en]

Despite its known expression in both the vascular endothelium and the lung epithelium, until recently the physiological role of the adhesion receptor Gpr116/ADGRF5 has remained elusive. We generated a new mouse model of constitutive Gpr116 inactivation, with a large genetic deletion encompassing exon 4 to exon 21 of the Gpr116 gene. This model allowed us to confirm recent results defining Gpr116 as necessary regulator of surfactant homeostasis. The loss of Gpr116 provokes an early accumulation of surfactant in the lungs, followed by a massive infiltration of macrophages, and eventually progresses into an emphysemalike pathology. Further analysis of this knockout model revealed cerebral vascular leakage, beginning at around 1.5 months of age. Additionally, endothelial-specific deletion of Gpr116 resulted in a significant increase of the brain vascular leakage. Mice devoid of Gpr116 developed an anatomically normal and largely functional vascular network, surprisingly exhibited an attenuated pathological retinal vascular response in a model of oxygen-induced retinopathy. These data suggest that Gpr116 modulates endothelial properties, a previously unappreciated function despite the pan-vascular expression of this receptor. Our results support the key pulmonary function of Gpr116 and describe a new role in the central nervous system vasculature.

National Category
Immunology in the medical area Cardiac and Cardiovascular Systems
Identifiers
urn:nbn:se:uu:diva-265915 (URN)10.1371/journal.pone.0137949 (DOI)000361792100023 ()26394398 (PubMedID)
Funder
EU, European Research Council, 294556EU, European Research Council, ITN-2012-317250-VESSELSwedish Cancer SocietySwedish Research CouncilKnut and Alice Wallenberg Foundation
Available from: 2015-11-04 Created: 2015-11-04 Last updated: 2018-04-07
Shang, M.-M., Talukdar, H. A., Hofmann, J. J., Niaudet, C., Asl, H. F., Jain, R. K., . . . Björkegren, J. L. (2014). Lim domain binding 2: a key driver of transendothelial migration of leukocytes and atherosclerosis. Arteriosclerosis, Thrombosis and Vascular Biology, 34(9), 2068-2077
Open this publication in new window or tab >>Lim domain binding 2: a key driver of transendothelial migration of leukocytes and atherosclerosis
Show others...
2014 (English)In: Arteriosclerosis, Thrombosis and Vascular Biology, ISSN 1079-5642, E-ISSN 1524-4636, Vol. 34, no 9, p. 2068-2077Article in journal (Refereed) Published
Abstract [en]

OBJECTIVE: Using a multi-tissue, genome-wide gene expression approach, we recently identified a gene module linked to the extent of human atherosclerosis. This atherosclerosis module was enriched with inherited risk for coronary and carotid artery disease (CAD) and overlapped with genes in the transendothelial migration of leukocyte (TEML) pathway. Among the atherosclerosis module genes, the transcription cofactor Lim domain binding 2 (LDB2) was the most connected in a CAD vascular wall regulatory gene network. Here, we used human genomics and atherosclerosis-prone mice to evaluate the possible role of LDB2 in TEML and atherosclerosis.

APPROACH AND RESULTS: mRNA profiles generated from blood macrophages in patients with CAD were used to infer transcription factor regulatory gene networks; Ldlr(-/-)Apob(100/100) mice were used to study the effects of Ldb2 deficiency on TEML activity and atherogenesis. LDB2 was the most connected gene in a transcription factor regulatory network inferred from TEML and atherosclerosis module genes in CAD macrophages. In Ldlr(-/-)Apob(100/100) mice, loss of Ldb2 increased atherosclerotic lesion size ≈2-fold and decreased plaque stability. The exacerbated atherosclerosis was caused by increased TEML activity, as demonstrated in air-pouch and retinal vasculature models in vivo, by ex vivo perfusion of primary leukocytes, and by leukocyte migration in vitro. In THP1 cells, migration was increased by overexpression and decreased by small interfering RNA inhibition of LDB2. A functional LDB2 variant (rs10939673) was associated with the risk and extent of CAD across several cohorts.

CONCLUSIONS: As a key driver of the TEML pathway in CAD macrophages, LDB2 is a novel candidate to target CAD by inhibiting the overall activity of TEML.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-294925 (URN)10.1161/ATVBAHA.113.302709 (DOI)24925974 (PubMedID)
Available from: 2016-05-30 Created: 2016-05-30 Last updated: 2017-05-11Bibliographically approved
Gaengel, K., Niaudet, C., Hagikura, K., Siemsen, B. L., Muhl, L., Hofmann, J. J., . . . Betsholtz, C. (2012). The Sphingosine-1-Phosphate Receptor S1PR1 Restricts Sprouting Angiogenesis by Regulating the Interplay between VE-Cadherin and VEGFR2. Developmental Cell, 23(3), 587-599
Open this publication in new window or tab >>The Sphingosine-1-Phosphate Receptor S1PR1 Restricts Sprouting Angiogenesis by Regulating the Interplay between VE-Cadherin and VEGFR2
Show others...
2012 (English)In: Developmental Cell, ISSN 1534-5807, E-ISSN 1878-1551, Vol. 23, no 3, p. 587-599Article in journal (Refereed) Published
Abstract [en]

Angiogenesis, the process by which new blood vessels arise from preexisting ones, is critical for embryonic development and is an integral part of many disease processes. Recent studies have provided detailed information on how angiogenic sprouts initiate, elongate, and branch, but less is known about how these processes cease. Here, we show that S1PR1, a receptor for the blood-borne bioactive lipid sphingosine-1-phosphate (S1P), is critical for inhibition of angiogenesis and acquisition of vascular stability. Loss of S1PR1 leads to increased endothelial cell sprouting and the formation of ectopic vessel branches. Conversely, S1PR1 signaling inhibits angiogenic sprouting and enhances cell-to-cell adhesion. This correlates with inhibition of vascular endothelial growth factor-A (VEGF-A)-induced signaling and stabilization of vascular endothelial (VE)-cadherin localization at endothelial junctions. Our data suggest that S1PR1 signaling acts as a vascular-intrinsic stabilization mechanism, protecting developing blood vessels against aberrant angiogenic responses.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-182752 (URN)10.1016/j.devcel.2012.08.005 (DOI)000308776400015 ()
Available from: 2012-10-18 Created: 2012-10-15 Last updated: 2017-12-07Bibliographically approved
Organisations

Search in DiVA

Show all publications