Sox9 is required for heart valve remodeling

Endocardial cushions (ECs) remodel to form heart valves composed of organized extracellular matrix (ECM) that shares characteristics with cartilage, tendon and bone. Aberrations in ECM are associated with valve disease, however the etiology is undefined. In developing cartilage BMP2 regulates Sox9, a transcription factor essential for cartilage formation that binds regulatory elements of proteoglycan (PG) genes. In remodeling heart valves, BMP2 treatment activates Sox9 and the cartilage PG gene Aggrecan, suggesting parallel regulatory mechanisms of Sox9 during limb and valve development. The in vivo role of Sox9 during valve remodeling was determined by loss of Sox9 function in subpopulations of cells during different stages of valve development in het. (del/+) and homo. (del/del) Sox9Flox mice bred with Col2a1‐ or Tie2‐cre+/− mice. Sox9Col2a1del/+ mice with reduced Sox9 in cells on the ventricularis surface of the valve leaflets are viable but display thickening of adult valve leaflets with accumulation of PG, associated with potential valve dysfunction. This is in contrast to reduced Sox9 function in all valve precursor cells in Sox9Tie2del/+ mice that appear normal. However Sox9Tie2del/Tie2del mice die in utero displaying ECs that fail to remodel, shortened limbs lacking digits and cleft palate. These structures show a dramatic reduction in PG deposition shown by Alcian blue staining, suggesting roles for Sox9 in these structures. In addition this study has generated mice with malformations in adult and embryonic valve structures that can be used to study etiology of valve disease. AHA Fellowship 0425366B.