Cystine import and oxidative catabolism fuel nutrient-responsive histone acetylation to unlock chromatin at endothelial cell loci and ensure vascular growth and repair [MLEC_WT_CSE-KO_ATAC_ext251]

Endothelial metabolic reprogramming is essential for vascular growth and critical for organ (re)generation, health and life span. Here, we identify a nuclear oxidative catabolic pathway that links cystine metabolism to endothelial gene regulation and angiogenesis. Endothelial cells preparing to proliferate, increase the translation of the transporter (SLC)7A11 to import cystine, which is further oxidatively catabolized by cystathionine gamma lyase (CSE) within the nuclear compartment. This process, preserved in young but not aged tissues, generates acetyl moieties in a pyruvate dehydrogenase dependent manner and initiates specific histone H3 lysine acetylation, leading to chromatin reorganization. Such changes solidify endothelial cell transcriptional programmes and maintain cell proliferation. Combined deletion of the SLC7A11 and CSE causes embryonic lethality and abrogates vascular growth. While SLC7A11 deficiency triggers compensatory de novo cysteine synthesis from methionine, partially preserving angiogenesis; CSE deletion disrupts nuclear cystine oxidative catabolism, endothelial transcription, and vessel formation. Therapeutically, oral cystine supplementation in models of retinopathy of prematurity, acute myocardial infraction and vascular injury in aging promotes vascular growth and repair. Together, our study highlights the role of cyst(e)ine nuclear oxidative catabolism in robust control of endothelial gene transcription, vessel growth and repair.