Neuroinflammation and Cardiovascular Function Notes

Neuroinflammation and Cardiovascular Function

Central Cardiovascular Control

• Key Areas: Brain areas critical for cardiovascular control include:
  • Circumventricular organs (CVOs)
  • Brain stem circuits

Circumventricular Organs (CVOs)

• Definition: Highly vascularized structures around the 3rd and 4th ventricles, characterized by the absence of a blood-brain barrier (BBB).
• Sensory CVOs:
  • Organum vasculosum of the lamina terminalis (OVLT)
  • Subfornical organ (SFO)
  • Area postrema (AP)
• Function:
  • Points of communication between blood, brain parenchyma, and CSF.
  • Neurons and glia express various receptors and ion channels to receive signals from circulating blood.
  • Critical for sodium and water balance, cardiovascular regulation, energy metabolism, and immunomodulation.

Central vs. Peripheral Capillaries

• Structural Differences:
  • Central capillaries lack fenestrations.
  • More extensive tight junctions (TJ).
• Functional Differences:
  • Impermeable to most substances.
  • Sparse pinocytic vesicular transport.
  • Increased expression of transport and carrier proteins (receptor-mediated endocytosis).
  • No gap junctions, only tight junctions.
  • Limited paracellular and transcellular transport.

SFO and Blood Pressure Regulation

• Inhibiting the SFO leads to a drop in blood pressure, indicating its role in maintaining blood pressure.
• Acronyms:
  • LPK: Lewis polycystic kidney rat
  • rSNA: renal sympathetic nerve activity
  • sSNA: splanchnic sympathetic nerve activity
  • lSNA: lumbar sympathetic nerve activity
  • ISO: isoguvacine – GABAA receptor agonist (inhibits cells)
  • Kyn: kynurenate (kynurenic acid) – antagonist at inotropic glutamate receptors (AMPA, NMDA, and kainate).

CNS Innervation of Sympathetic Outflow

• Stimulation of the RVLM increases BP and SNA.

Summary of Brain Centers

• Multiple brain centers, including CVOs, brain stem nuclei, and hypothalamus, play an important role in cardiovascular function regulation.
• These centers are well-characterized regarding their function and interaction with the immune system.

Immune System and Cardiovascular Control

• Neuroinflammation can influence cardiovascular function and blood pressure.

Bone Marrow and Brain Link

• A link exists between the brain and bone marrow.
• Elevated Inflammatory Markers in Bone Marrow:
  • Observed in spontaneously hypertensive rats and AngII infusion models.
  • Increased mRNA levels of pro-inflammatory cytokines in BM-derived mononuclear cells in hypertensive rats compared to normotensive rats.
  • Elevated levels of chemokine CCL2 (aka MCP-1) in bone marrow, serum, and cerebrospinal fluid (CSF).

BM Reconstitution - Chimeric Rats

• Pro-inflammatory mediators are increased in hypertensive animals compared to normotensive animals.
• Bone marrow from hypertensive animals substituted into normotensive animals and vice versa affects blood pressure.
• Bone marrow transfer confirmed by reconstituting bone marrow from male rats into female rats and testing for the Y-chromosome in mononuclear cells.

Microglia in Chimeric Rats

• Activated microglia in the hypothalamic paraventricular nucleus (PVN) are decreased in spontaneously hypertensive rats (SHRs) after reconstitution with Wistar-Kyoto (WKY) bone marrow.
• Activated microglia indicate neuroinflammation.

Inhibition of Microglia in SHR and Ang II Hypertension

• Minocycline is used to inhibit microglia activation, specifically polarization to the M1 phenotype.
• Administration of minocycline to SHRs significantly decreases blood pressure, suggesting a role of microglia in blood pressure regulation.

Proposed Mechanism for Neuroinflammation's Impact on Hypertension

1. Pro-hypertensive signals such as angiotensin II (Ang II) activate PVN pre-autonomic neurons, increasing sympathetic nerve activity (SNA) and causing the release of C-C chemokine ligand 2 (CCL2).
2. Increased SNA affects the bone marrow (BM), resulting in an increase in inflammatory cells (IC) and a decrease in angiogenic progenitor cells (APCs).
3. This imbalance is associated with vascular pathology and an increase in blood pressure.
4. Inflammatory progenitors migrate to the PVN due to increased neuronal release of CCL2, where they differentiate into BM-derived microglia/macrophages.
5. Both resting microglia and BM-derived microglia/macrophages are activated to release cytokines and chemokines.

Key Inflammatory Mediators and CV Function

• Learning objective: Describe key inflammatory mediators involved in signaling in CV control circuits.

Cytokines in the Subfornical Organ (SFO)

• SFO is a CVO without a BBB, located on the anterior wall of the 3V.
• High expression of AngII receptors; stimulation elicits a drinking response.
• Sends projections to both paraventricular nucleus compartments to modulate SNA and AVP release.
• Body fluid homeostasis and blood pressure are linked.

Effects of TNF-α in the SFO

• Direct microinjections of TNF-α into the SFO of anesthetized rats cause a rise in blood pressure and heart rate.
• Responses attenuated by:
  • Captopril: ACE inhibitor
  • Losartan: AT1 receptor antagonist
  • NS-398: selective COX2 inhibitor

Effects of IL-1β in the SFO

• Direct microinjections of IL-1β into the SFO of anesthetized rats elicit a rise in blood pressure and heart rate, comparable to TNF-α.
• Responses attenuated by:
  • Captopril: ACE inhibitor
  • Losartan: AT1 receptor antagonist
  • NS-398: selective COX2 inhibitor
• These experiments suggest interactions between inflammatory cytokines (TNF-α and IL-1β) and the Angiotensin system.

Cytokines in the Area Postrema (AP)

Effects of TNF-α in the AP

• Microinjection of TNF-α into the area postrema of anesthetized rats elicits an increase in resting blood pressure.
• The effect of TNF-α is dose-dependent.
• This response is abolished by pre-treatment with a TNFR1 receptor-specific antibody.

Effects of TNFR1 Antagonism in Hypertension

• Microinjection of TNFR1 receptor blocking antibody into the area postrema of anesthetized hypertensive (2K-1C) rats elicits a significant fall in blood pressure.
• This effect was not observed in sham (non-hypertensive) rats, suggesting a role of TNF-α in hypertensive animals.

Proposed Mechanism: AngII and Neuroinflammation

1. Primary (neurogenic) and secondary (renal stenosis, diet) causes increase circulating AngII levels.
2. Increase in AngII causes increases in circulating CCL2 (MCP-1).
3. Causes changes in the brain (disruption of the BBB, infiltration of immune cells, activation of microglia).
4. Immune cells and activated microglia release inflammatory factors including IL-6, TNF-α, IL-1β, and CCL2.
5. Exacerbates neuroinflammation, disrupts homeostasis, and activates premotor neurons.
6. Leads to an increase in SNA and hypertension.

Gut Microbiota, Neuroinflammation, and Hypertension

Gut-Brain Communication

• Neural, immunological, and metabolic pathways facilitate gut microbiota's influence on the brain.
• Mechanisms:
  • Enteroendocrine cell release of gut hormones.
  • Cytokine release from mucosal immune cells.
  • Bacterial products such as SCFA, GABA, or 5-HT precursors.
  • Afferent neural pathways, including the vagus nerve.
  • Stress hormones (NA) might influence bacterial gene expression; signaling between bacteria might change microbial composition.

Microbiota-Microglia Link

• Germ-free (GF) mice exhibit abnormal microglia compared to specific pathogen-free (SPF) mice.

SCFA Restores Microglia Morphology

Proposed Mechanism: Gut Microbiota and Hypertension

1. Ang II, Salt, or Aldosterone-induced hypertension leads to microglia activation.
2. Drives an increase in SNA from areas such as the paraventricular nucleus of the hypothalamus (PVN).
3. This drives a change in gut microbiota and increased gut permeability.
4. Results in oxidative stress, changes in microbial products, stimulation of inflammatory cells, and release of cytokines.
5. Feeds back to potentially further exacerbate neuroinflammation and hypertension.