SWI/SNF chromatin-remodeling enzymes Brahma-related gene 1 (BRG1) and Brahma (BRM) are dispensable in multiple models of postnatal angiogenesis but are required for vascular integrity in infant mice

Mammalian SWItch/Sucrose NonFermentable (SWI/SNF) adenosine triphosphate (ATP)-dependent chromatin-remodeling complexes play important roles in embryonic vascular development by modulating transcription of specific target genes. We sought to determine whether SWI/SNF complexes likewise impact postnatal physiological and pathological angiogenesis.

Despite their important roles in embryonic vascular development, SWI/SNF chromatin-remodeling complexes display a surprising lack of participation in the 3 models of postnatal angiogenesis we analyzed. However, these complexes are essential for maintaining vascular integrity in specific tissue beds before weaning. These findings highlight the temporal and spatial specificity of SWI/SNF activities in the vasculature and may indicate that other chromatin-remodeling complexes play redundant or more essential roles during physiological and pathological postnatal vascular development.

Brahma-related gene 1 (BRG1) and Brahma gene (BRM) are ATPases within mammalian SWI/SNF complexes and are essential for the complexes to function. Using mice with vascular-specific mutations in Brg1 or with a global mutation in Brm, we employed 3 models to test the role of these ATPases in postnatal angiogenesis. We analyzed neonatal retinal angiogenesis, exercise-induced angiogenesis in adult quadriceps muscles, and tumor angiogenesis in control and mutant animals. We found no evidence of defective angiogenesis in Brg1 or Brm mutants using these 3 models. Brg1/Brm double mutants likewise show no evidence of vascular defects in the neonatal retina or tumor angiogenesis models. However, 100% of Brg1/Brm-double mutants in which Brg1 deletion is induced at postnatal day 3 (P3) die by P19 with hemorrhaging in the small intestine and heart. Conclusions: Despite their important roles in embryonic vascular development, SWI/SNF chromatin-remodeling complexes display a surprising lack of participation in the 3 models of postnatal angiogenesis we analyzed. However, these complexes are essential for maintaining vascular integrity in specific tissue beds before weaning. These findings highlight the temporal and spatial specificity of SWI/SNF activities in the vasculature and may indicate that other chromatin-remodeling complexes play redundant or more essential roles during physiological and pathological postnatal vascular development.