Endothelial cross-talks in the aging heart

  • Cardiovascular diseases are still regarded as the main cause of death in the modern world. However, the generic term "cardiovascular diseases" is not uniformly defined. It essentially describes diseases of the cardiovascular system and includes diseases such as hypertension, arteriosclerosis, myocardial infarctions, heart failure, coronary heart diseases, rheumatic heart diseases and heart valve defects. In addition to the well-known risk factors such as obesity, smoking, hypercholesterolemia and lack of exercise, age is a further risk factor that plays an important role in the development of cardiovascular diseases. As the modern societies age; this becomes an increasing problem. But why does the prevalence of cardiovascular diseases increase with age? In gen-eral, age-dependent changes at the cellular level are assumed to be responsible for the pathological changes in the cardiac and vascular tissues. Important mechanisms such as autophagy, oxidative stress, mitochondrial dysfunctions, genomic instability, cellular senescence and disturbances in signaling pathways of growth factors play a decisive role. In old age, myocardial hypertrophy occurs, which results in cardiac wall thickening and an altered geometry of the ventricle. Chronic inflammations, paracrine and age-dependent cell-intrinsic factors further lead to activation of cardiac fibro-blasts with increase cell proliferation, collagen secretion and matrix cross-linking. The consequences are interstitial and perivascular fibrosis, which stiffen the heart and blood vessels. Oxidative stress and inflammations additionally attack the blood ves-sels and impair endothelial function, which is further aggravated by possible pre-existing conditions such as diabetes mellitus and hypertension. In the past decades, the main focus has therefore been on researching these age-dependent changes in the hope of better understanding cardiovascular ageing and developing possible regenerative interventions. By studying the repair mechanisms of other organs such as the lungs and the bone marrow, the endothelium in particular showed a high regenerative capacity, which influences the proliferation and cell func-tion of the surrounding cells. For a long time, the general opinion was that the endothelium is only the internal lin-ing of blood and lymphatic vessels, as well as the heart chambers, which as a single-layer barrier guarantees the integrity of the blood vessels. However, endothelial cells are very heterogeneous, depending on the type of blood vessel and the type of tis-sue they serve. In addition to their barrier function, endothelial cells also regulate the exchange of substances between blood and tissue, stimulate the formation of new blood vessels and re-model existing vascular networks. They are also able to re-structure the extracellular matrix that surrounds them. They release not only matrix proteins, but also cytokines and growth factors into the extracellular space. On de-mand, these factors are then released and stimulate angiogenesis or cell prolifera-tion. In addition, the secretion of various matrix proteins not only stabilizes the cellu-lar neighborhood, but also regulates various cell functions. By modelling the endothelial environment - the so-called vascular niche - endothelial cells are able to communicate with the surrounding cells. As a result, a regenerative effect of the vascular niche has already been described in various organs. In the liv-er, for example, it has been shown that increased concentrations of endothelial Ang2 and decreased endothelial activin A after partial hepatectomy stimulate the prolifera-tion of hepatocytes and thus liver regeneration. In the bone marrow, endothelial cells mobilize stem cells via nitric oxide and in the lungs, endothelial MMP14 releases growth factors from the extracellular matrix, which stimulate epithelial cell prolifera-tion after partial pneumectomy. Whether such a regenerative effect of the vascular niche also plays a role in the heart is largely unknown. Since both the regenerative capacity of the heart and endothelial function decrease with age, the aim of this dissertation was to investigate the role of the vascular niche and endothelial cell communication in the aged heart. Human cell lines as well as mouse and artificial rat models were used for these investigations. Since this thesis is a cumulative dissertation with partially published papers, it is divided into three parts. In the first part of this thesis, the transcriptional signature of secretory genes in the aged cardiac endothelium was studied. Perfused endothelial cells from hearts of young (12-week-old animals) and old mice (20-month-old animals) were isolated and used for bulk RNA sequencing. The two matrix proteins laminin β1 and β2 were among the top-regulated genes. While laminin β2 was particularly expressed in the young cardiac endothelium, laminin β1 was predominantly found in the old endotheli-um. This change in laminin expression was confirmed histologically at protein level and its autocrine function was investigated in vitro. To mimic the in vivo situation in vitro, cell culture dishes were coated with human recombinant laminin 421 or laminin 411 and sutured with human endothelial cells from the umbilical vein (HUVEC). Di-verse functional investigations showed that endothelial cells migrated and adhered poorly in the presence of laminin 411, while in Matrigel tube formation assays HU-VEC formed reduced endothelial networks when cultured on LM 411. ...

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Author:Julian Uwe Gabriel WagnerORCiDGND
Place of publication:Frankfurt am Main
Referee:Stefanie DimmelerORCiDGND, Amparo Acker-PalmerORCiDGND
Advisor:Stefanie Dimmeler
Document Type:Doctoral Thesis
Date of Publication (online):2020/08/20
Year of first Publication:2019
Publishing Institution:Universitätsbibliothek Johann Christian Senckenberg
Granting Institution:Johann Wolfgang Goethe-Universität
Date of final exam:2020/08/20
Release Date:2020/08/28
Page Number:220
Dewey Decimal Classification:5 Naturwissenschaften und Mathematik / 57 Biowissenschaften; Biologie / 570 Biowissenschaften; Biologie
Sammlung Biologie / Biologische Hochschulschriften (Goethe-Universität)
Licence (German):License LogoDeutsches Urheberrecht