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New findings What is the central question of this study? What is the role of the renin-angiotensin system with angiotensin II acting via its receptor AT1a in spinal cord injury-induced cardiac atrophy? What is the main finding and its importance? Knockout of AT1a did not protect mice that had undergone thoracic level 4 transection from cardiac atrophy. There were no histopathological signs but there was reduced load-dependent left ventricular function (lower stroke volume and cardiac output) with preserved ejection fraction. Abstract Spinal cord injury (SCI) leads to cardiac atrophy often accompanied by functional deficits. The renin-angiotensin system (RAS) with angiotensin II (AngII) signalling via its receptor AT1a might contribute to cardiac atrophy post-SCI. We performed spinal cord transection at thoracic level T4 (T4-Tx) or sham-operation in female wild-type mice (WT, n = 27) and mice deficient in AT1a (Agtr1a-/- , n = 27). Echocardiography (0, 7, 21 and 28 days post-SCI) and histology and gene expression analyses at 1 and 2 months post-SCI were performed. We found cardiac atrophy post-SCI: reduced heart weight, reduced estimated left ventricular mass in Agtr1a-/- , and reduced cardiomyocyte diameter in WT mice. Although, the latter as well as stroke volume (SV) and cardiac output (CO) were reduced in Agtr1a-/- mice already at baseline, cardiomyocyte diameter was even smaller in injured Agtr1a-/- mice compared to injured WT mice. SV and CO were reduced in WT mice post-SCI. Ejection fraction and fractional shortening were preserved post-SCI in both genotypes. There were no histological signs of fibrosis and pathology in the cardiac sections of either genotype post-SCI. Gene expression of Agtr1a showed a trend for up-regulation at 2 months post-SCI; angiotensinogen was up-regulated at 2 month post-SCI in both genotypes. AngII receptor type 2 (Agtr2) was up- and down-regulated at 1 and 2 months post-SCI in WT mice, respectively, and Ang-(1-7) receptor (Mas) at 1 and 2 months post-SCI. Atrogin-1/MAFbx and MuRF1, atrophy markers, were not significantly up-regulated post-SCI. Our data show that lack of AT1a does not protect from cardiac atrophy post-SCI.

Spinal cord injury (SCI) above mid-thoracic levels leads to autonomic dysfunction affecting both the cardiovascular system and thermoregulation. The renin-angiotensin system (RAS) which is a potent regulator of blood pressure, including its novel beneficial arm with the receptor Mas could be an interesting target in post-SCI hemodynamics. To test the hypothesis that hemodynamics, activity and diurnal patterns of those are more affected in the Mas deficient mice post-SCI we used a mouse model of SCI with complete transection of spinal cord at thoracic level 4 (T4-Tx) and performed telemetric monitoring of blood pressure (BP) and heart rate (HR). Our data revealed that hypothermia deteriorated physiological BP and HR control. Preserving normothermia by keeping mice at 30°C prevented severe hypotension and bradycardia post-SCI. Moreover, it facilitated rapid return of diurnal regulation of BP, HR and activity in wild type (WT) mice. In contrast, although Mas deficient mice had comparable reacquisition of diurnal HR rhythm, they showed delayed recovery of diurnal rhythmicity in BP and significantly lower nocturnal activity. Exposing mice with T4-Tx (kept in temperature-controlled cages) to 23°C room temperature for one hour at different time-points post-SCI, demonstrated their inability to maintain core body temperature, Mas deficient mice being significantly more impaired than WT littermates. We conclude that Mas deficient mice were more resistant to acute hypotension, delayed nocturnal recovery, lower activity and more severely impaired thermoregulation. The ambient temperature had significant effect on hemodynamics and, thus it should be taken into account when assessing cardiovascular parameters post-SCI in mice.

The chemokine CXCL12/SDF-1 is crucial for heart development and affects cardiac repair processes due to its ability to attract leukocytes and stem cells to injured myocardium. However, there is a great controversy whether CXCL12 is beneficial or detrimental after myocardial infarction (MI). The divergence in the reported CXCL12 actions may be due to the cellular source and time of release of the chemokine after MI. This study was designed to evaluate the role of cardiomyocyte-derived CXCL12 for cardiogenesis and heart repair after MI. We generated two rodent models each targeting CXCL12 in only one cardiac cell type: cardiomyocyte-specific CXCL12-overexpressing transgenic (Tg) rats and CXCL12 conditional knockout (cKO) mice. Animals of both models did not show any signs of cardiac abnormalities under baseline conditions. After induction of MI, cKO mice displayed preserved cardiac function and remodeling. Moreover, fibrosis was less pronounced in the hearts of cKO mice after MI. Accordingly, CXCL12 Tg rats revealed impaired cardiac function post-MI accompanied by enhanced fibrosis. Furthermore, we observed decreased numbers of infiltrating Th1 cells in the hearts of cKO mice. Collectively, our findings demonstrate that cardiomyocyte-derived CXCL12 is not involved in cardiac development but has adverse effects on the heart after injury via promotion of inflammation and fibrosis. • CXCL12 in cardiomyocytes is not involved in cardiac development. • CXCL12 deficiency in cardiomyocytes improves outcome of myocardial infarction. • CXCL12 overexpression in cardiomyocytes worsens outcome of myocardial infarction. • CXCL12 increases fibrosis and invasion of Th1 cells in the heart after infarction.

Based on its trophic effects on neurons and vascular cells, vascular endothelial growth factor (VEGF) is a promising candidate for the treatment of neurodegenerative diseases. To evaluate the therapeutic potential of VEGF, we here examined effects of this growth factor on the degeneration of axotomized retinal ganglion cells (RGCs), which, as CNS-derived neurons, offer themselves in an excellent way to study neuroprotectionin vivo. Making use of a transgenic mouse line that constitutively expresses human VEGF under a neuron-specific enolase promoter, we show that (1) the VEGF-transgenic retina overexpresses human VEGF, (2) RGCs carry the VEGF receptor-2, and (3) vascular networks in normal and axotomized VEGF-transgenic (tg) retinas do not differ from control animals. After axotomy, RGCs of VEGF-tg mice were protected against delayed degeneration, as compared with wild-type littermates. Western blots revealed increased phosphorylated ERK-1/2 and Akt and reduced phosphorylated p38 and activated caspase-3 levels in axotomized VEGF-transgenic retinas. Intravitreous injections of pharmacological ERK-1/2 (PD98059) or Akt (LY294002) inhibitors showed that VEGF exerts neuroprotection by dual activation of ERK-1/2 and Akt pathways. In view that axotomy-induced RGC death occurs slowly and considering that RGCs are CNS-derived neurons, we predict the clinical implementation of VEGF in neurodegenerative diseases of both brain and retina.