Adrenomedullin: A vasoactive agent for sporadic and hereditary vascular cognitive impairment

Fig. 1. Signaling pathway of adrenomedullin (AM) in cells forming the blood-brain barrier. AM binds to a heterodimer receptor composed of the calcitonin receptor-like receptor (CLR) and receptor activity-modifying protein type 2 (RAMP2) or 3 (RAMP3), termed AM1 and AM2 receptors, respectively. Upregulation of AM in endothelial cells by hypoxic-ischemic injury, shear stress, or proinflammatory cytokines induces angiogenesis through activation of Akt, MAPK, and FAK in an autocrine manner. AM directly binds to AM receptors on vascular smooth muscle cells (SMCs) and induces SMC migration and vasodilation. AM also promotes differentiation of oligodendrocyte precursor cells into mature oligodendrocytes under hypoxic conditions. These activities may synergistically serve as protective factors, mitigating against cerebrovascular diseases such as ischemic stroke and vascular cognitive impairment. Abbreviations: cAMP, adenosine 3′,5′-cyclic monophosphate; cGMP, guanosine 3′,5′-cyclic monophosphate; eNOS, endothelial nitric oxide synthase; ERK, extracellular signal-regulated kinase; FAK, focal adhesion kinase; IP3, inositol triphosphate; MEK, mitogen-activated protein kinase; NO, nitric oxide;…

Fig. 2. Schematic diagram of the interactions between major cellular components within the brain white matter (WM). WM microvessels are associated with astrocytes, oligodendrocyte precursor cells (OPCs), microglia/macrophages and pericytes. The gliovascular unit of the WM is formed by astrocyte end feet juxtaposed to the WM endothelium. Glial and endothelial cells functionally interact with each other in a paracrine manner. Together with astrocytes, pericytes are important players within the gliovascular unit and modulate vessel diameter. The oligovascular niche is formed by OPCs and the endothelium, where an exchange of soluble signals (e.g. trophic factors such as adrenomedullin (AM) or chemical messengers) plays an important role in sustaining oligodendrocyte homeostasis and WM integrity. Microglial processes are closely associated with the brain endothelium in a fraction of cerebral microvessels and patrol vasculature in the central nervous system.