Transcriptomic profiling of vegfc(hy-/-);vegfd(-/-) mutant hearts reveals that vegfc/d signaling and lymphatics vasculature play a role in cardiac metabolism
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ABSTRACT:
ORGANISM(S): Danio rerio
PROVIDER: GSE133131 | GEO | 2019/09/03
REPOSITORIES: GEO
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Project description:Recent studies have suggested that promoting lymphangiogenesis enhances cardiac repair following injury, but it is unknown whether lymphangiogenesis is required for cardiac regeneration. Here, we describe the anatomical distribution, regulation and function of the cardiac lymphatic network in a highly regenerative zebrafish model system using transgenic reporter lines and loss-of-function approaches.To understand the transcriptional profile of the model, we performed RNA-seq on cardiac ventricles from control and mutant (vegfc(hy-/-);vegfd(-/-)) ventricles. Overall, vegfc(hy-/-;vegfd-/-) mutant ventricles were characterized by an up-regulation of pathways related to sphingolipid and phospholipid metabolism, translation, protein maturation and nonsense mediated decay compared to control hearts. Our findings suggest that lymphatics vasculature play a role in lipid transport and when lymphatic function is compromised in vegfch(y-/-;vegfd-/-) mutant, there are consequences to sphingolipid and phospholipid metabolism. Vegfc(hy-/-;vegfd-/-) mutant ventricles were not characterized by an enrichment of genes pathways implicated in pathological hypertrophy. This finding suggests that the absence of cardiac lymphatics induced a physiological rather than pathological cardiac hypertrophy.
2019-09-03 | GSE133130 | GEO
Project description:Transcriptomic profiling of vegfc(hy-/-) vegfd(-/-) mutant hearts reveals that vegfc/d signaling and lymphatics vasculature play a role in cardiac metabolism
| PRJNA550046 | ENA
Project description:Transcriptomic profiling of vegfc(hy-/-) vegfd(-/-) mutant hearts reveals that vegfc/d signaling and lymphatics vasculature play a role in cardiac metabolism [fresh tissue]
| PRJNA550048 | ENA
Project description:To determine whether lymphangiogenesis is required for cardiac regeneration, vegfc(hy-/-);vegfd(-/-) double mutants and control hearts were collected and analyzed at 180 days after cryoinjury, this corresponds to a time point when the regenerative response is normally completed in wild-type zebrafish. Surprisingly, the vast majority (~70%) of vegfc(hy-/-);vegfd(-/-) mutants, which completely lack cardiac lymphatics, were able to mount a complete regenerative response without any signs of fibrosis. We found that the cardiac regenerative response was impaired only in a subset (3/8) of vegfc(hy-/-);vegfd(-/-) mutants, which were characterized by large deposits of fibrotic scar tissue present at the injury site. To profile vegfc/d-dependent genetic pathways contributing to lymphangiogenesis in cardiac regeneration, we performed RNA-seq on cryosections from control and mutant ventricles at 180 days following cryoinjury. Overall, vegfc(hy-/-);vegfd(-/-) mutant ventricles were characterized by an up-regulation of pathways related to metabolism, inflammation, hemostasis, negative regulation of FGFR signaling, translation, protein maturation and nonsense mediated decay compared to control hearts. These findings are consistent with the cardiac hypertrophy phenotype in vegfc(hy-/-);vegfd(-/-) mutants. To determine the molecular basis of the regenerative capacity within the mutant fish population, we next compared the transcriptional profiles of vegfc(hy-/-);vegfd(-/-) mutant hearts that did not regenerate (n=3) with the profiles of mutant hearts which recovered completely (n=5) at 180 days post cryoinjury. The subset of vegfc(hy-/-);vegfd(-/-) mutant hearts that failed to regenerate were characterized by an enrichment of inflammatory pathways, in particular TRAF6-mediated IRF7 activation, interferon alpha beta signaling and regulation of IFNA signaling. These findings suggest that loss of the vegfc/d signaling axis causes a sustained and pronounced inflammatory response following injury. This change in the cardiac micro-environment seems to favor adverse conditions which impair the regenerative process.
2019-09-03 | GSE133129 | GEO
Project description:The lymphatic vasculature mediates essential physiological functions including fluid homeostasis, lipid and hormone transport, and immune cell trafficking. Recent studies have suggested that promoting lymphangiogenesis enhances cardiac repair following injury, but it is unknown whether lymphangiogenesis is required for cardiac regeneration. Here, we describe the anatomical distribution, regulation, and function of the cardiac lymphatic network in a highly regenerative zebrafish model system using transgenic reporter lines and loss-of-function approaches. We show that zebrafish lacking functional vegfc and vegfd signaling are devoid of a cardiac lymphatic network and display cardiac hypertrophy in the absence of injury, suggesting a role for these vessels in cardiac tissue homeostasis. Using two different cardiac injury models, we report a robust lymphangiogenic response following cryoinjury, but not following apical resection injury. Although the majority of mutants lacking functional vegfc and vegfd signaling were able to mount a full regenerative response even in the complete absence of a cardiac lymphatic vasculature, cardiac regeneration was severely impaired in a subset of mutants, which was associated with heightened pro-inflammatory cytokine signaling. These findings reveal a context-dependent requirement for the lymphatic vasculature during cardiac growth and regeneration.
| S-EPMC6706389 | biostudies-literature
Project description:Identifying coronary artery progenitors and their developmental pathways could inspire novel regenerative treatments for heart disease. Multiple sources of coronary vessels have been proposed, including the sinus venosus (SV), endocardium and proepicardium, but their relative contributions to the coronary circulation and the molecular mechanisms regulating their development are poorly understood. We created an ApjCreER mouse line as a lineage-tracing tool to map SV-derived vessels onto the heart and compared the resulting lineage pattern with endocardial and proepicardial contributions to the coronary circulation. The data showed a striking compartmentalization to coronary development. ApjCreER-traced vessels contributed to a large number of arteries, capillaries and veins on the dorsal and lateral sides of the heart. By contrast, untraced vessels predominated in the midline of the ventral aspect and ventricular septum, which are vessel populations primarily derived from the endocardium. The proepicardium gave rise to a smaller fraction of vessels spaced relatively uniformly throughout the ventricular walls. Dorsal (SV-derived) and ventral (endocardial-derived) coronary vessels developed in response to different growth signals. The absence of VEGFC, which is expressed in the epicardium, dramatically inhibited dorsal and lateral coronary growth but left vessels on the ventral side unaffected. We propose that complementary SV-derived and endocardial-derived migratory routes unite to form the coronary vasculature and that the former requires VEGFC, revealing its role as a tissue-specific mediator of blood endothelial development.
| S-EPMC4302936 | biostudies-literature
Project description:Infectious myocarditis is the result of an immune response to a microbial infection of the heart. The blood vessels of the heart, both the intramyocardial microvasculature and the large epicardial coronary arteries, play an important role in the pathogenesis of infectious myocarditis. First of all, in addition to cardiomyocytes, endothelial cells of the cardiac (micro)vasculature are direct targets for infection. Moreover, through the expression of adhesion molecules and antigen presenting Major Histocompatibility Complex molecules, the blood vessels assist in shaping the cellular immune response in infectious myocarditis. In addition, damage and dysfunction of the cardiac (micro)vasculature are associated with thrombus formation as well as aberrant regulation of vascular tone including coronary vasospasm. These in turn can cause cardiac perfusion abnormalities and even myocardial infarction. In this review, we will discuss the role of the cardiac (micro)vasculature in the pathogenesis of infectious myocarditis.
| S-EPMC6010496 | biostudies-literature
Project description:Vertebrate retinal development requires timely and precise fusion of the optic fissure (OF). Failure of this event leads to congenital vision impairment in the form of coloboma. Recent studies have suggested hyaloid vasculature to be involved in OF fusion. In order to examine this link, we analyzed OF fusion and hyaloid vasculogenesis in the zebrafish pax2a noi mutant line. We first determined that pax2a-/- embryos fail to accumulate F-actin in the OF prior to basement membrane (BM) degradation. Furthermore, using 3D and live imaging we observed reduced OF hyaloid vascularization in pax2a-/- embryos. When examining the connection between pax2a loss of function and hyaloid vasculature, we observed significant reduction of talin1 expression, a regulator of hyaloid vasculature. In addition, cranial VEGF expression was found to be reduced in pax2a-/- embryos. Pharmacological inhibition of VEGF signaling phenocopied the pax2a-/- vasculature, F-actin and BM degradation phenotypes. Lastly, we determined that OF associated hyaloid vasculature is a source of mmp2, mmp14a and mmp14b expression and showed that mmp2 is functionally necessary for degradation of OF BM. Taken together we propose a pax2a driven mechanism that ensures proper and timely hyaloid vasculature invasion of the OF in order to facilitate availability of the BM remodeler mmp2.
| S-EPMC7311462 | biostudies-literature
Project description:Obesity is a key risk factor for metabolic and cardiovascular diseases, and although we understand the mechanisms regulating weight and energy balance, the causes of some forms of obesity remain enigmatic. Despite the well-established connections between lymphatics and lipids, and the fact that intestinal lacteals play key roles in dietary fat absorption, the function of the lymphatic vasculature in adipose metabolism has only recently been recognized. It is well established that angiogenesis is tightly associated with the outgrowth of adipose tissue, as expanding adipose tissue requires increased nutrient supply from blood vessels. Results supporting a crosstalk between lymphatic vessels and adipose tissue, and linking lymphatic function with metabolic diseases, obesity, and adipose tissue, also started to accumulate in the last years. Here we review our current knowledge of the mechanisms by which defective lymphatics contribute to obesity and fat accumulation in mouse models, as well as our understanding of the lymphatic-adipose tissue relationship.
| S-EPMC5629116 | biostudies-literature
Project description:Transcriptomic profiling of non-regenerative vegfc(hy-/-) vegfd(-/-) mutant hearts reveals a marked inflammatory response [fixed tissue]
| PRJNA550047 | ENA