Pericyte and Astrocyte Dysfunction in Long COVID: Key Insights for Family Physicians

Author: Based on original work by Dr Graham Exelby Date: September 05, 2025

Purpose: This summary distils the complex role of pericytes and astrocytes in Long COVID for family physicians. It emphasizes practical recognition of symptoms, underlying mechanisms, and management strategies to support primary care decision-making.

Abstract

Long COVID often presents with persistent neurological symptoms like cognitive impairment ("brain fog"), fatigue, post-exertional malaise (PEM), and autonomic instability. This paper focuses on dysfunction in pericytes (vascular support cells) and astrocytes (neuronal support cells) as key drivers.

Key findings:

• Pericytes, targeted by SARS-CoV-2 via ACE2 and RAGE receptors, detach and constrict capillaries, leading to reduced brain blood flow and inflammation.

• Astrocytes become reactive, causing glutamate imbalance, poor waste clearance (glymphatic impairment), and sustained swelling.

• This forms a self-perpetuating cycle explaining chronic symptoms, with overlaps to ME/CFS, POTS, and fibromyalgia.

• Implications for family physicians: View Long COVID as a neurovascular issue. Use history and simple tests for early identification; refer for imaging or specialists as needed.

Introduction and Pathophysiological Framework

Long COVID affects multiple systems, but brain-related symptoms are common and debilitating. The "neurovascular unit" (blood vessels, pericytes, astrocytes, and neurons) is disrupted, leading to ongoing inflammation, low oxygen (hypoxia), and waste buildup.

Pericytes and astrocytes work together: Pericytes stabilize vessels and control flow; astrocytes clear waste and balance brain chemistry. In Long COVID, virus or inflammation damages them, creating loops of vascular injury, glial overactivity, and immune activation (via NLRP3 inflammasome).

For family physicians: Patients may report "head pressure" (worse upright), slow thinking, or crashing after minimal activity (PEM). This aligns with reduced brain perfusion seen on scans (SPECT/PET). Consider Long COVID in post-COVID patients with unexplained neurology.

Pericyte Disruption: Gatekeepers of Vascular Homeostasis

Pericytes are critical for blood-brain barrier (BBB) integrity and flow regulation.

In Long COVID:

• Viral/inflammatory attack: High ACE2/RAGE expression makes them susceptible; spike protein causes constriction and detachment.

• Consequences: Leaky BBB, reduced perfusion (hypoperfusion) in areas like thalamus/brainstem, and recruitment of immune cells via CCL2.

• Amplifiers: Ongoing RAGE activation sustains inflammation; hypoxia and microclots worsen dropout.

Clinical manifestations: Brain fog, fatigue, dizziness, PEM—often positional.

Physician tip: Check orthostatic vitals (BP/HR changes on standing). If positive, suspect POTS overlap, check with NASA Lean test. Blood markers like IL-6 or D-dimer may indicate inflammation/clotting (CRP may be suppressed).

Astrocyte Reactivity: Amplifiers of Neuroimmune Dysfunction

Astrocytes support neurons by managing glutamate, water balance (via AQP4), and waste drainage (glymphatics).

In Long COVID:

• Triggered by pericytes: Leaks expose them to stressors, leading to "A1" reactive state (pro-inflammatory).

• Key issues: Excess glutamate (excitotoxicity), cytokine release (IL-6, CCL2), mitochondrial failure, and glymphatic block.

• Outcomes: Waste accumulation, brain pressure, energy deficits.

Symptoms: PEM, sleep issues, sensory overload, mood changes, chronic pain.

Physician tip: Inquire about unrefreshing sleep or worsening after mental effort. Differentiate from depression/anxiety, but note overlaps.

A Triphasic Evolution

Pathology progresses:

1. Acute: Direct viral hit on pericytes, initial leaks/clots.

2. Subacute: Pericyte loss activates astrocytes.

3. Chronic: Reactive loops cause scarring, persistent hypoperfusion.

Evidence: Brain imaging shows hypometabolism; studies link to NLRP3 (inflammation hub).

Interplay and Clinical Correlates

Pericytes and astrocytes interact: Pericyte damage stresses astrocytes, amplifying cycles.

Symptom clusters:

• Cognitive (brain fog): Thalamic hypoperfusion, glutamate excess.

• PEM/fatigue: Energy failure, lactate buildup.

• Autonomic (tachycardia, breathlessness): Brainstem hypoxia.

• Head pressure: Glymphatic/venous congestion.

Table: Symptom Drivers

Symptom/Cluster	Primary Driver
Brain fog, slow cognition	Thalamic hypoperfusion, glutamate excess
PEM, exertional collapse	Astrocyte metabolic failure, lactate excess
Sensory hypersensitivity	Glial priming, reduced filtering
Sleep dysfunction	Brainstem–astrocyte GABA and vagal loss
Head pressure, visual symptoms	Venous congestion, glymphatic obstruction
Tachycardia, breathlessness	Brainstem hypoxia, reduced preload, vagal loss

Overlaps: Similar to fibromyalgia/ME/CFS—assess holistically.

Therapeutic Implications

No cure yet, but target phases:

• Early: H1/H2 blockade, LDN

• Intermediate: Reduce inflammation (e.g., LDN, Omega 3), telmisartan for hypoxia.

• Chronic: Support drainage (manual lymphatic therapy), metabolism (tirzepatide off-label?), repair (peptides—experimental).

Physician advice:

• Diagnosis: History key; exclude mimics (e.g., thyroid, anaemia). Use tools like NASA Lean Test for orthostasis.

• Management: Pacing, hydration, compression stockings.

• Holistic: Nutrition (avoid food body reacts to, look at low histamine and/or low glutamate diet trials,) appropriate physical therapy especially lymphatic when head pressure is present, psychology. Monitor for mood/suicide risk.

• Future: Biomarker-guided therapies emerging.   DNA valuable if you can use it- seek resource to assist in interpretation and linking with the immunometabolic dysfunction.

This hypothesis reframes Long COVID as treatable neurovascular pathology.   References available on request.