Angiomodulin (IGFBP7) is a cerebral specific angiocrine factor, but is probably not a blood–brain barrier inducer

Abstract

Background: Several secreted factors have been identified as drivers of cerebral vasculature development and inducers of blood-brain barrier (BBB) differentiation. Vascular endothelial growth factor A (VEGF-A) is central for driving cerebral angiogenesis and Wnt family factors (Wnt7a, Wnt7b and norrin) are central for induction and maintenance of barrier properties. Expressed by developing neural tissue (neuron and glia progenitors), they influence the formation of central nervous system (CNS) vascular networks. Another type of factors are tissue-specific paracrine factors produced by endothelial cells (ECs), also known as 'angiocrine' factors, that provide instructive signals to regulate homeostatic and regenerative processes. Very little is known about CNS angiocrine factors and their role in BBB development. Angiomodulin (AGM) was reported to be expressed by developing vasculature and by pathological tumor vasculature. Here we investigated AGM in the developing CNS and its function as a potential BBB inducer. Methods:We analyzed microarray data to identify potential angiocrine factors specifically expressed at early stages of barrier formation. We then tested AGM expression with immunofluorescence and real-time PCR in various organs during development, post-natal and in adults. Permeability induction with recombinant proteins (Miles assay) was used to test potential interaction of AGM with VEGF-A. Results: Several angiocrine factors are differentially expressed by CNS ECs and AGM is a prominent CNS-specific angiocrine candidate. Contrary to previous reports, we found that AGM protein expression is specific to developing CNS endothelium and not to highly angiogenic developing vasculature in general. In skin vasculature we found that AGM antagonizes VEGF-A-induced vascular hyperpermeability. Finally, CNS AGM expression is not specific to BBB vasculature and AGM is highly expressed in non-BBB choroid-plexus vasculature. Conclusions:We propose AGM as a developmental CNS vascular-specific marker. AGM is not a pan-endothelial marker, nor a general marker for developing angiogenic vasculature. Thus, AGM induction in the developing CNS might be distinct from its induction in pathology. While AGM is able to antagonize VEGF-A-induced vascular hyperpermeability in the skin, its high expression levels in non-BBB CNS vasculature does not support its potential role as a BBB inducer. Further investigation including loss-of-function approaches might elucidate AGM function in the developing CNS.

Targeting ductal-endothelial crosstalk alleviate pancreatitis

“…However, the cell-cell communication between VECs and pancreatic resident cells remain largely unexplored. In other organs, such as bone marrow, brain and liver, VEC release several angiocrine factors to target the tissue resident cells to mediate organ development and regeneration (43)(44)(45)(46)(47). Hematopoietic stem/progenitor cells, astrocyte and cardiomyocyte derived signals are reported to induce differentiation of VEC and angiogenesis (17,48,49).…”

Association of lipoproteins and thyroid hormones with cognitive dysfunction in patients with systemic lupus erythematosus

“…In a new study in 2021, IGFBP7 was reported to be related to lipid metabolism in nonalcoholic fatty liver disease (NAFLD) [ 55 ]. In addition, it is also involved in the development of a variety of brain diseases [ 98 – 100 ]. In our results, IGFBP7 showed a negative correlation with figure copy scores, indicating that IGFBP7 might be related to visuospatial/constructional dysfunction in patients with SLE.…”

An Integrated Transcriptome Analysis Reveals IGFBP7 Upregulation in Vasculature in Traumatic Brain Injury

“…IGFBP7 is highly expressed in the vasculature during development in the central nervous system. But, in adults, the IGFBP7 expression was reported to be only restricted to smooth muscle cells covering large vessels and choroid plexus vasculature, which is characterized by limited BBB property and high permeability ( Hooper et al, 2009 ; Bar et al, 2020 ). Increased IGFBP7 expression in vasculature was observed in brain pathological conditions including glioblastoma and stroke, as well as other types of tumors ( Hooper et al, 2009 ; Dieterich et al, 2012 ; Buga et al, 2014 ; Komiya et al, 2014 ).…”