Background:
Heart valves regulate the unidirectional forward flow and prevent retrograde backflow of blood during the cardiac cycle. Cardiac valve disease (CVD) is observed in approximately 2.5% of the general population and the incidence increases to ~10% in elderly people. Patients with severe CVD require surgery and effective pharmacological treatments are currently not available. PROX1 is a transcription factor that regulates the development of lymphatic, venous, and lymphovenous valves (vascular valves). We identified that PROX1 is also expressed in a subset of valvular endothelial cells (VECs) that are located on the downstream (fibrosa) side of cardiac valves. Whether PROX1 regulates cardiac valve development and disease is not known.
Method and Results:
We have discovered that mice lacking
Prox1
in their VECs (
Prox1
ΔVEC
) develop enlarged aortic and mitral valves in which the expression of proteoglycans is increased (control, N=10;
Prox1
ΔVEC
, N=9,
p
<0.05). Echocardiography revealed moderate to severe stenosis of aortic valves of
Prox1
ΔVEC
mice (control, N=5;
Prox1
ΔVEC
, N=9,
p
<0.05). PROX1 regulates the expression of the transcription factor FOXC2 in the vascular valves. Similarly, we have found that the expression of FOXC2 is downregulated in the VECs of
Prox1
ΔVEC
mice. Specific knockdown of FOXC2 in VECs results in the thickening of aortic valves (control, N=10;
shFoxc2
ΔVEC
, N=8,
p
<0.05). Furthermore, restoration of FOXC2 expression in VECs (
Foxc2
OE-VEC
) ameliorates the thickening of the aortic valves of
Prox1
ΔVEC
mice (
Prox1
ΔVEC
,
N=9; Foxc2
OE-VEC
;
Prox1
ΔVEC
, N=8,
p
<0.05). We have also determined that the expression of platelet-derived growth factor-B (
Pdgfb
) is increased in the valve tissue of
Prox1
ΔVEC
mice and in PROX1 deficient sheep mitral valve VECs (MVECs) (siCtrl
,
N=4;
siProx1
, N=4,
p
<0.05). Additionally, hyperactivation of PDGF-B signaling in mice results in a phenotype that is similar to
Prox1
ΔVEC
mice (control
,
N=4;
Pdgfb
GOF
, N=3,
p
<0.05).
Conclusion:
Together these data suggest that PROX1 maintains the extracellular matrix composition of cardiac valves by regulating the expressions of FOXC2 and PDGF-B in VECs.
Transcription factor genes Smad4 and Gata4 cooperatively regulate cardiac valve development
