Adrenomedullin-RAMP2 and -RAMP3 Systems Regulate Cardiac Homeostasis during Cardiovascular Stress

Endocrinology. 2021 Mar 1;162(3):bqab001. doi: 10.1210/endocr/bqab001.


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 (KO) (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 1 week of transverse aortic constriction (TAC), however, C-RAMP2-/- exhibited significant cardiac hypertrophy, decreased ejection fraction, and increased fibrosis compared with 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 compared with 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.

Keywords: adrenomedullin; cardiac fibrosis; cardiac hypertrophy; heart failure; lymphatic vessel; mitochondria.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adrenomedullin / metabolism
  • Adrenomedullin / physiology*
  • Animals
  • Animals, Newborn
  • Cardiomegaly / genetics
  • Cardiomegaly / metabolism
  • Cardiomegaly / pathology
  • Cardiomegaly / physiopathology
  • Cardiovascular System / metabolism
  • Cardiovascular System / pathology
  • Cardiovascular System / physiopathology*
  • Cells, Cultured
  • Constriction, Pathologic
  • Coronary Stenosis / genetics
  • Coronary Stenosis / metabolism
  • Coronary Stenosis / pathology
  • Coronary Stenosis / physiopathology
  • Hemodynamics / genetics
  • Homeostasis / genetics
  • Mice
  • Mice, Knockout
  • Myocytes, Cardiac / pathology
  • Myocytes, Cardiac / physiology
  • Oxidative Stress / genetics
  • Receptor Activity-Modifying Protein 2 / genetics
  • Receptor Activity-Modifying Protein 2 / metabolism
  • Receptor Activity-Modifying Protein 2 / physiology
  • Receptor Activity-Modifying Protein 3 / genetics
  • Receptor Activity-Modifying Protein 3 / metabolism
  • Receptor Activity-Modifying Protein 3 / physiology
  • Receptor Activity-Modifying Proteins / genetics
  • Receptor Activity-Modifying Proteins / metabolism
  • Receptor Activity-Modifying Proteins / physiology*
  • Signal Transduction / genetics
  • Signal Transduction / physiology
  • Stress, Physiological / physiology*


  • Ramp2 protein, mouse
  • Ramp3 protein, mouse
  • Receptor Activity-Modifying Protein 2
  • Receptor Activity-Modifying Protein 3
  • Receptor Activity-Modifying Proteins
  • Adrenomedullin