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An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Although mitochondrial activity is critical for angiogenesis, its mechanism is not entirely clear. Here we show that mice with endothelial deficiency of any one of the three nuclear genes encoding for mitochondrial proteins, transcriptional factor (TFAM), respiratory complex IV component (COX10), or redox protein thioredoxin 2 (TRX2), exhibit retarded retinal vessel growth and arteriovenous malformations (AVM). Single-cell RNA-seq analyses indicate that retinal ECs from the three mutant mice have increased TGFβ signaling and altered gene expressions associated with vascular maturation and extracellular matrix, correlating with vascular malformation and increased basement membrane thickening in microvesels of mutant retinas. Mechanistic studies suggest that mitochondrial dysfunction from Tfam, Cox10, or Trx2 depletion induces a mitochondrial localization and MAPKs-mediated phosphorylation of SMAD2, leading to enhanced ALK5-SMAD2 signaling. Importantly, pharmacological blockade of ALK5 signaling or genetic deficiency of SMAD2 prevented retinal vessel growth retardation and AVM in all three mutant mice. Our studies uncover a novel mechanism whereby mitochondrial dysfunction via the ALK5-SMAD2 signaling induces retinal vascular malformations, and have therapeutic values for the alleviation of angiogenesis-associated human retinal diseases.

Cerebral cavernous malformations (CCMs) are vascular abnormalities that primarily occur in adulthood and cause cerebral hemorrhage, stroke, and seizures. CCMs are thought to be initiated by endothelial cell (EC) loss of any one of the three Ccm genes: CCM1 (KRIT1), CCM2 (OSM), or CCM3 (PDCD10). Here we report that mice with a brain EC-specific deletion of Pdcd10 (Pdcd10BECKO) survive up to 6-12 months and develop bona fide CCM lesions in all regions of brain, allowing us to visualize the vascular dynamics of CCM lesions using transcranial two-photon microscopy. This approach reveals that CCMs initiate from protrusion at the level of capillary and post-capillary venules with gradual dissociation of pericytes. Microvascular beds in lesions are hyper-permeable, and these disorganized structures present endomucin-positive ECs and α-smooth muscle actin-positive pericytes. Caveolae in the endothelium of Pdcd10BECKO lesions are drastically increased, enhancing Tie2 signaling in Ccm3-deficient ECs. Moreover, genetic deletion of caveolin-1 or pharmacological blockade of Tie2 signaling effectively normalizes microvascular structure and barrier function with attenuated EC-pericyte disassociation and CCM lesion formation in Pdcd10BECKO mice. Our study establishes a chronic CCM model and uncovers a mechanism by which CCM3 mutation-induced caveolae-Tie2 signaling contributes to CCM pathogenesis., Animal models that fully recapitulate human CCM pathogenesis are not currently available. Here, the authors establish a novel CCM model and reveal that caveolae-Tie2 signaling is involved in CCMs formation at the level of venules, which is accompanied by gradual dissociation of pericytes.

Regulation of VEGFR2 represents an important mechanism for the control of angiogenesis. VEGFR2 activity can be regulated by post-translational modifications such as ubiquitination and acetylation. However, whether VEGFR2 can be regulated by SUMOylation has not been investigated. Here we show that endothelial-specific deletion of the SUMO endopeptidase SENP1 reduces pathological angiogenesis and tissue repair during hindlimb ischemia, and VEGF-induced angiogenesis in the cornea, retina, and ear. SENP1-deficient endothelial cells show increased SUMOylation of VEGFR2 and impaired VEGFR2 signalling. SUMOylation at lysine 1270 retains VEGFR2 in the Golgi and reduces its surface expression, attenuating VEGFR2-dependent signalling. Moreover, we find that SENP1 is downregulated and VEGFR2 hyper-SUMOylated in diabetic settings and that expression of a non-SUMOylated form of VEGFR2 rescues angiogenic defects in diabetic mice. These results show that VEGFR2 is regulated by deSUMOylation during pathological angiogenesis, and propose SENP1 as a potential therapeutic target for the treatment of diabetes-associated angiogenesis., VEGFR2 is a central regulator of angiogenesis. Here Zhou et al. report that SUMOylation of VEGFR2 regulates its subcellular localisation and activity, and that endothelial-specific knockout of the SUMO endopeptidase SENP1 protects against VEGFR2-mediated pathological angiogenesis.

Data from clinical research and our previous study have suggested the potential involvement of SENP1, the major protease of post-translational SUMOylation, in cardiovascular disorders. Here, we investigate the role of SENP1-mediated SUMOylation in graft arteriosclerosis (GA), the major cause of allograft failure. We observe an endothelial-specific induction of SENP1 and GATA2 in clinical graft rejection specimens that show endothelial activation-mediated vascular remodelling. In mouse aorta transplantation GA models, endothelial-specific SENP1 knockout grafts demonstrate limited neointima formation with attenuated leukocyte recruitment, resulting from diminished induction of adhesion molecules in the graft endothelium due to increased GATA2 SUMOylation. Mechanistically, inflammation-induced SENP1 promotes the deSUMOylation of GATA2 and IκBα in endothelial cells, resulting in increased GATA2 stability, promoter-binding capability and NF-κB activity, which leads to augmented endothelial activation and inflammation. Therefore, upon inflammation, endothelial SENP1-mediated SUMOylation drives GA by regulating the synergistic effect of GATA2 and NF-κB and consequent endothelial dysfunction., A major cause of transplanted organ failure is graft arteriosclerosis. Qiu et al. show that a key protease of post-translational SUMO modification, SENP1, is crucial for graft arteriosclerosis by regulating the activity of GATA2 transcription factor in the endothelium, and promoting endothelial inflammation and alloimmunity.

Adipocyte dysfunction correlates with the development of diabetes. Here we show that mice with a adipocyte-specific deletion of the SUMO-specific protease SENP1 gene develop symptoms of type-1 diabetes mellitus (T1DM), including hyperglycaemia and glucose intolerance with mild insulin resistance. Peri-pancreatic adipocytes from SENP1-deficient mice exhibit heightened NF-κB activity and production of proinflammatory cytokines, which induce CCL5 expression in adjacent pancreatic islets and direct cytotoxic effects on pancreatic islets. Mechanistic studies show that SENP1 deletion in adipocytes enhances SUMOylation of the NF-κB essential molecule, NEMO, at lysine 277/309, leading to increased NF-κB activity, cytokine production and pancreatic inflammation. We further show that NF-κB inhibitors could inhibit pre-diabetic cytokine production, β-cell damages and ameliorate the T1DM phenotype in SENP1-deficient mice. Feeding a high-fat diet augments both type-1 and type-2 diabetes phenotypes in SENP1-deficient mice, consistent with the effects on adipocyte-derived NF-κB and cytokine signalling. Our study reveals previously unrecognized mechanism regulating the onset and progression of T1DM associated with adipocyte dysfunction., Pro-inflammatory NF-κB signalling is regulated by protein sumoylation. Here the authors show that lack of the desumoylating protease SENP1 in fat tissue induces NF-κB activity and inflammation in peri-pancreatic adipocytes, leading to symptoms of type 1 diabetes in mice.