A Distinct Role of the Autonomic Nervous System in Modulating the Function of Lymphatic Vessels under Physiological and Tumor-Draining Conditions
2019; 27 (11): 3305-+
An in vivo wound healing model for the characterization of the angiogenic process and its modulation by pharmacological interventions.
2019; 9 (1): 6004
Lymphatic vessels (LVs) are important in the regulation of tissue fluid homeostasis and the pathogenesis of tumor progression. We investigated the innervation of LVs and the response to agonists and antagonists of the autonomic nervous system in vivo. While skin-draining collecting LVs express muscarinic, α1- and β2-adrenergic receptors on lymphatic endothelial cells and smooth muscle cells, intestinal lacteals express only β-adrenergic receptors and muscarinic receptors on their smooth muscle cells. Quantitative in vivo near-infrared imaging of the exposed flank-collecting LV revealed that muscarinic and α1-adrenergic agonists increased LV contractility, whereas activation of β2-adrenergic receptors inhibited contractility and initiated nitric oxide (NO)-dependent vasodilation. Tumor-draining LVs were expanded and showed a higher innervation density and contractility that was reduced by treatment with atropine, phentolamine, and, most potently, isoproterenol. These findings likely have clinical implications given the impact of lymphatic fluid drainage on intratumoral fluid pressure and thus drug delivery.
View details for DOI 10.1016/j.celrep.2019.05.050
View details for Web of Science ID 000470993200017
View details for PubMedID 31189113
View details for PubMedCentralID PMC6581737
EMMPRIN and its ligand Cyclophilin A as novel diagnostic markers in inflammatory cardiomyopathy
INTERNATIONAL JOURNAL OF CARDIOLOGY
2013; 163 (3): 299–304
Angiogenesis during wound healing is essential for tissue repair and also affected during cancer treatment by anti-angiogenic drugs. Here, we introduce a minimally invasive wound healing model in the mouse ear to assess angiogenesis with high spatiotemporal resolution in a longitudinal manner in vivo using two-photon microscopy in mice expressing GCaMP2 in arterial endothelial cells. The development of vascular sprouts occurred in a highly orchestrated manner within a time window of 8 days following wounding. Novel sprouts developed exclusively from the distal stump of the transsected arteries, growing towards the proximal arterial stump. This was in line with the incidence of Ca2+ transients in the arterial endothelial cells, most probably a result of VEGF stimulation, which were more numerous on the distal part. Functional analysis revealed perfusion across the wound site via arterial sprouts developed between days 6 and 8 following the incision. At day 8, proximal and distal arteries were structurally and functionally connected, though only 2/3 of all sprouts detected were actually perfused. Treatment with the FDA approved drug, sunitinib, the preclinical drug AZD4547, as well as with the combination of the two agents had significant effects on both structural and functional readouts of neo-angiogenesis. The simplicity and high reproducibility of the model makes it an attractive tool for elucidating migratory activity, phenotype and functionality of endothelial cells during angiogenesis and for evaluating specific anti-angiogenic drug interventions.
View details for DOI 10.1038/s41598-019-42479-1
View details for PubMedID 30979919
View details for PubMedCentralID PMC6461656
During inflammatory cardiomyopathy matrix metalloproteinases are crucially involved in cardiac remodeling. The aim of the present study was to investigate whether the "extracellular matrix metalloproteinase inducer" EMMPRIN (CD147) and its ligand Cyclophilin A (CyPA) are upregulated in inflammatory cardiomyopathy and may serve as diagnostic markers. Therefore, a series of 102 human endomyocardial biopsies were analyzed for the expression of EMMPRIN and CyPA and correlated with histological and immunohistological findings.Endomyocardial biopsies were stained for EMMPRIN and CyPA in addition to standard histology (HE, Trichrom) and immunohistological stainings (MHC-II, CD68, CD3). 39 (38.2%) biopsies met the immunohistological criteria of an inflammatory cardiomyopathy. EMMPRIN, which was predominantly expressed on cardiomyocytes, was slightly (but significantly) upregulated in non inflammatory cardiomyopathies compared to normal histopathological findings and highly upregulated in inflammatory cardiomyopathy compared to both non inflammatory cardiomyopathy and normal histopathology. In contrast, CyPA reveals no enhanced expression in non inflammatory cardiomyopathies and a highly enhanced expression in inflammatory cardiomyopathy, where it is closely associated with leucocytes infiltrates. We found a strong correlation between both EMMPRIN and CyPA with the expression of MHC-II molecules (correlation coefficient 0.475 and 0.527, p<0.05). Moreover, we found a correlation for both EMMPRIN and CyPA with CD68 (correlation coefficient 0.393 and 0.387, p<0.05) and CD3 (correlation coefficient 0.360 and 0.235, p<0.05).EMMPRIN is enhanced in both inflammatory and non inflammatory cardiomyopathies and can serve as a marker of myocardial remodeling. CyPA may represent a novel and specific marker for cardiac inflammation.
View details for DOI 10.1016/j.ijcard.2011.06.049
View details for Web of Science ID 000315156000019
View details for PubMedID 21724278