Figure 3: Mechanisms involved in hypertensive response sensitization (HTRS) and neuroplasticity.

By studying changes after the induction of HTRS, important memory-related molecular changes have been identified that are maintained until the end of the delay period. Many neural systems involve ‘signature’ neurotransmitters or neuromodulatory mechanisms. For example, substance P and calcitonin gene-related peptide and their receptors are ubiquitous in pain signaling pathways^97,98,242. As components of the brain renin–angiotensin–aldosterone system (RAAS) are upregulated after induction of hypertensive response sensitization (HTRS), RAAS components might reasonably be considered a signature of the pathways controlling sympathetic tone and blood pressure. Considerable evidence indicates that glutamate and glutamate receptors are critically involved in nearly all forms of neuroplasticity^243,244, and most cells in the nervous system express at least one type of glutamate receptor²⁴⁵. This neurotransmitter depolarizes neurons by acting on ionotropic N-methyl-D-aspartate (NMDA) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors. Most, if not all, cells in the network controlling sympathetic tone have both NMDA and AMPA receptors and receive glutamatergic input from other network neurons. Growth factors have multiple roles in neuroplasticity including altering membrane potentials, increasing protein synthesis, promoting cell viability, and morphological changes. Brain-derived neurotrophic factor (BDNF, probably the best-studied CNS growth factor) is associated with almost every aspect of neural and functional plasticity²⁴⁶ and acts through TrkB (also known as BDNF/NT3 growth factors receptor). Finally, long-term neuroplastic changes require the synthesis of new proteins, which requires activation of transcription factors, including c-Fos, FOSB and cAMP response element-binding protein (CREB). Red rectangles indicate signaling mechanisms implicated in the neuroplasticity underlying HTRS²⁴⁷. In future work, it will be important to determine how many structures in the neural network controlling sympathetic tone and blood pressure manifest detectable changes and how long such changes persist. Figure based on and modified from REF.¹¹⁶.