Data from: Adrenomedullin-RAMP2 and -RAMP3 systems regulate cardiac homeostasis during cardiovascular stress

Adrenomedullin (AM) is a peptide hormone with multiple physiological
functions, which are regulated by its receptor activity-modifying
proteins, RAMP2 and RAMP3. We previously reported that AM or RAMP2
knockout (AM-/-, RAMP2-/-) is embryonically lethal in mice, whereas
RAMP3-/- mice are apparently normal. AM, RAMP2 and RAMP3 are all highly
expressed in the heart; however, their functions there are not fully
understood. Here, we analyzed the pathophysiological functions of the
AM-RAMP2 and AM-RAMP3 systems in hearts subjected to cardiovascular
stress. Cardiomyocyte-specific RAMP2-/- (C-RAMP2-/-) and
RAMP3-/- showed no apparent heart failure at base
line. After one week of transverse aortic constriction (TAC),
however, C-RAMP2-/- exhibited significant cardiac hypertrophy,
decreased ejection fraction and increased
fibrosis as compared
to wild-type mice. Both dP/dtmax and dP/dtmin
were significantly reduced in C-RAMP2-/-,
indicating reduced ventricular contractility and
relaxation. Exposing C‑RAMP2‑/-
cardiomyocytes to isoproterenol enhanced their hypertrophy and
oxidative stress as compared to wild-type cells. C‑RAMP2‑/- cardiomyocytes
also contained fewer viable mitochondria and
showed reduced mitochondrial membrane
potential and respiratory capacity. RAMP3-/-
also showed reduced systolic function and enhanced fibrosis after TAC, but
those only became apparent after 4 weeks. A reduction in cardiac
lymphatic vessels was the characteristic feature in RAMP3-/-. These
observations indicate the AM-RAMP2 system is necessary for early
adaptation to cardiovascular stress through regulation of cardiac
mitochondria. AM-RAMP3 is necessary for later adaptation through
regulation of lymphatic vessels. The AM-RAMP2 and AM-RAMP3 systems thus
play separate critical roles in the maintenance of cardiovascular
homeostasis against cardiovascular stress.