UCLA

Pulmonary hypertension (PH) is a rare, progressive and debilitating disease characterized by elevated pressure in the pulmonary circulation coupled with right ventricular hypertrophy and failure. Microglial and astrocytic activation mediated neuroinflammation in the brain and spinal cord has been implicated in the sympathetic nervous system (SNS) hyperactivity in experimental PH, however, the role and precise mechanism of the intricate interplay between neuroinflammation and SNS activation in PH is still unknown. In Chapter 2, we discovered that cardiopulmonary afferent signaling to the thoracic DRG and dorsal horn is mediated via TRPV1 and substance P in PH. Our first-ever transcriptomic analysis on the TSC of 2 clinically relevant rat models (MCT and SuHx) of severe PH and RVF delineated common dysregulated genes and pathways highlighting neuroinflammation and apoptosis. We observed microgliosis, astrogliosis and increased fractalkine expression in the TSC of both rat models and in human PAH. Elevated plasma norepinephrine in both rat models confirmed increased sympathoexcitation. Finally, intrathecal minocycline decreased TSC microglial count, activation, and expression of proinflammatory cytokines, and reduced sympathoexcitation resulting in rescue of PH-RVF. In Chapter 3, we demonstrated that intrathecal RTX administration abolished TRPV1 expression in the TSC and attenuated PH-RVF by decreasing cardiac sympathetic tone in MCT and SuHx rats. We also revealed that mechanistically, NMDAR-NOS1 mediated neuroinflammation and neuronal apoptosis in the TSC in PH is dependent on TRPV1 activation. Lung and RV RNASeq from RTX-treated MCT rats demonstrated reversal of fibrosis, inflammation and apoptosis. In Chapter 4, we expanded on our findings by investigating downstream of TRPV1 gene and found increased signature of glutamatergic and NOS1 signaling in the TSC of MCT and SuHx rats and patients with PAH. We demonstrated that NMDAR inhibition decreased TSC NOS1 expression, neuroinflammation, neuronal apoptosis and associated sympathoexcitation and rescued PH-RVF in MCT rats. Finally, pharmacological inhibition of NOS1 attenuated PH-RVF by reducing TSC neuroinflammation, neuronal apoptosis and sympathoexcitation. Moreover, lung and RV RNA-Seq from SMTC-treated MCT rats demonstrated reversal fibrosis, inflammation and apoptosis. Invitro analysis indicated that norepinephrine and SP may play major role in lung and RV reversal of EndMT and fibrosis in SMTC-treated MCT Rats. Taken together, this dissertation is a compilation of the first work investigating the mechanistic evidence of TSC neuroinflammation and its role in SNS hyperactivity in PH.