Results from my study have shown in 2022 the existence of telocytes (TCs) in mice ligamentum arteriosum (LA). Telocytes (TCs) are unique interstitial or stromal cells of mesodermal origin, defined by long cellular extensions called telopodes (Tps) which form a network, connecting them to surrounding cells. These Tps have dilated portions named podoms (usually containing mitochondria, endoplasmic reticulum and caveolae) and very thin segments (below resolving power of light microscopy), called podomers. Generally, transmission electron microscope revealed the existence of Tps with various conformations: (a) long, flattened irregular veils (ribbon‐like segments) with knobs, corresponding to podoms, and (b) tubular structures (podomers) with uneven caliber because of irregular dilations (knobs)—the podoms. Also shown were numerous extracellular vesicles and exosomes released by the TCs which sometimes made direct contact with telopodes. Telopodes were observed communicating with each other through adherens junctions. Telopodes sandwiched between myocytes or in close proximity (0.01 μm) from nerve terminals were also observed. These data might be useful for understanding the role(s) of TCs in intercellular signaling and communication, neuromodulation as well as comprehension of pathologies like structural remodeling within the LA.
Ductus arteriosus is a muscular artery in fetal circulation, spanning from the bifurcation of the pulmonary trunk to the aortic arch, shunting blood directly from pulmonary circulation into systemic circulation thus by‐passing the fluid‐filled lungs. Postnatally, it changes name to the ligamentum arteriosum (LA), when a cascade of anatomical and physiological processes leads to its closure. Though the LA has generally been considered as a fibrosed remnant of the ductus arteriosus, anecdotal and contradictory reports still describe the LA as a small muscular artery. We hypothesized the likelihood of contractile muscular elements retainment in this so‐called ligament. To investigate this, mediastinum of wild‐type mouse, pig, and human LA were subjected to routine and special histological staining, single‐immunolabeling, electron microscopy (mouse and pig only), and tension recording of explanted pig LA in organ bath experiments. Contrary to a canonical ligament, the LA was mainly made up of α‐smooth muscle actin‐positive cells in all three species, confirmed by routine and special histological staining as well as transmission electron microscopy. Myocytes within the LA contracted in response to exogenous noradrenalin (NA). NA‐induced precontracted LA relaxed upon administration of the α1‐adrenergic blockers (prazosin and tamsulosin). Though the LA does not function in its original capacity as fetal shunt, it is clearly not a passive structure, and may be described as muscular and contractile. The contractile abilities of LA myocytes may act on the two great vessels to which it is attached causing a change in their distensibility.
Marfan syndrome (MFS) is a prevalent inherited connective tissue disorder associated with premature mortality due to thoracic aortic aneurysms and subsequent fatal aortic events. Current treatment options improve outcomes only partially and better preventive pharmacotherapies are needed. By utilizing patient samples and animal disease models, we herein demonstrate that leukocyte-derived myeloperoxidase (MPO) critically contributes to disease progression. MFS patients and mice displayed increased circulating MPO levels as well as marked aortic MPO deposition compared to controls. Mechanistically, MPO induced inflammatory endothelial activation and endothelial-to-mesenchymal transition which triggered aortic leukocyte recruitment. Furthermore, MPO directly contributed to adverse extracellular matrix remodeling by promoting oxidative stress and nitrosylation of extracellular matrix proteins. Genetic MPO deficiency and pharmacological MPO inhibition attenuated MFS-related aneurysm formation. We herein identify MPO as a critical mediator of MFS-related thoracic aortic aneurysm formation and a promising target to influence disease progression.
Introduction The ligamentum arteriosum (LA) is generally described as a mere fibrotic remnant of the embryonic bypass (ductus arteriosus) from the pulmonary trunk to the aortic arch, obliterating soon after childbirth. There have been anecdotal and contradictory reports on this speculated morphological change. This study set out to elucidate the morphology, innervation, neurochemistry and function of LA. Method LA of human, pig, wild‐type and appropriate transgenic reporter mouse strains were studied using routine and special histological staining methods, single‐ and double‐immunofluorescence labeling using antibodies directed against structural markers such as α‐smooth muscle actin (αSMA) and protein gene product 9.5 (PGP 9.5), against neuropeptides such as neuropeptide Y (NPY), vasoactive intestinal peptide (VIP), substance P (SP), and calcitonin gene‐related peptide (CGRP), and against transmitter synthesizing enzymes such as tyrosine hydroxylase (TH; noradrenergic), choline acetyltransferase (ChAT; cholinergic), and nitric oxide synthase (NOS). Additionally, pig and mice LA were investigated using transmission electron microscopy (TEM). Organ bath experiments subjected pig LA to increasing cumulative doses of exogenous noradrenalin (NA), ɑ1‐adrenergic antagonists (tamsulosin and prazosin) and varying Hz of electrical field stimulation. Results Contrary to a canonical ligament, the LA was mainly made up by αSMA‐positive cells in all three species. TEM confirmed the presence of smooth muscle cells with caveolae, mmyofilaments’, dense bands etc. within the LA. The ligament received a noticeable amount of noradrenergic (TH, NPY) and sensory (CGRP, SP) but no cholinergic innervation in all three species investigated. The LA exhibited a dose‐ and frequency‐dependent contraction in response to cumulative doses of exogenous NA and electrical field stimulation respectively. Furthermore, NA pre‐contracted LA relaxed to baseline upon administration of ɑ1‐adrenergic antagoniststs (tamsulosin and prazosin). Conclusion The LA may not function in its original capacity as a foetal shunt but still retains smooth muscles cells until senescence. Ultra‐structurally, the presence of myofilaments, dense bodies and dense bands on smooth muscle cells (SMC) observed within the LA are findings compatible with the apparatus responsible for contraction in SMC. Furthermore, the presence of numerous mitochondria, a cellular organelle, and a potential site of calcium accumulation for smooth muscle contraction, observed within the LA may play a role in its contractility. Immunoreactivity to TH‐, NPY‐, SP‐, and CGRP‐ is suggestive of sympathetic and sensory innervation within the LA. Additionally, dose‐response contractility and relaxation of pre‐contracted LA to exogenous NA and ɑ1‐adrenergic antagonists in organ bath experiments suggests activity of ɑ1‐adrenoceptors. Conclusively, it is evident that LA is made up of contractile SMC with noradrenergic and sensory innervation. Its contractility may influence the compliance or impedance of t...
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