Ramp2, short for receptor activity-modifying protein 2, is a crucial protein that modulates the activity of many Family B GPCRs. It is associated with pathways related to blood sugar homeostasis, vascular and organ homeostasis, and is important for maintaining endothelial and cardiac homeostasis [1,2,4,5]. Genetic models, such as knockout mice, have been instrumental in studying its functions.

In knockout mouse models, deficiency in Ramp2, an adrenomedullin-receptor accessory protein, leads to vascular endothelial cell deformities that are embryonically lethal, indicating its key role in vascular integrity and homeostasis from prenatal stages through adulthood [2]. In cardiomyocyte-specific Ramp2 knockout (C-Ramp2-/-) mice, after transverse aortic constriction (TAC), significant cardiac hypertrophy, decreased ejection fraction, increased fibrosis, reduced ventricular contractility and relaxation, as well as enhanced oxidative stress and mitochondrial dysfunction were observed, suggesting the AM-Ramp2 system is necessary for early adaptation to cardiovascular stress [5]. In hepatocytes, the balance of Gata3 and Ramp2 regulates the proliferation of liver sinusoidal endothelial cells and hepatic revascularization during postoperative liver regeneration [3]. Also, mutant Ramp2 in mice disrupts the AM-Ramp2/CRLR-cAMP signaling pathway, leading to cAMP reduction and retinal ganglion cell death, causing primary open-angle glaucoma [6].

In conclusion, Ramp2 is essential for multiple biological functions including maintaining vascular and cardiac homeostasis, and is involved in processes like hepatic vascular reconstitution. The use of Ramp2 knockout and conditional knockout mouse models has significantly contributed to understanding its role in diseases such as vascular disorders, cardiac stress-related diseases, and primary open-angle glaucoma, providing insights into potential therapeutic targets.