Family 7: Vascular and Endothelial
Family overview. Vascular homeostasis requires intact endothelial function, appropriate vasomotor tone, barrier integrity, and matched perfusion to metabolic demand. Failure at any level produces hypoperfusion, barrier breach, or vascular wall pathology.
Concrete mechanisms and ME/CFS evidence:
Endothelial dysfunction. Impaired endothelial-dependent vasodilation; patient serum impairs endothelial cell function in vitro; reduced eNOS activity and NO bioavailability (Rivas et al. 2022).
Cerebral hypoperfusion. 91% of ME/CFS patients show abnormally reduced cardiac output and cerebral blood flow during tilt testing despite normal heart rate-blood pressure response — absent compensatory cerebral vasodilation, a functional signature of endothelial dysfunction specifically in cerebral vessels (Van Ness et al. 2024).
Impaired cerebrovascular autoregulation. The cerebral vasculature fails to maintain perfusion pressure during orthostatic stress; cannot compensate for reduced cardiac output.
Vascular permeability increase. Systemic vascular leakage from mast cell mediators, complement activation, and bradykinin contributes to third-spacing and reduced effective blood volume.
Blood-brain barrier compromise. Increased BBB permeability allows peripheral immune cells and inflammatory mediators to access CNS compartment; see also Family 10.
RAAS paradox and hypovolemia. ME/CFS patients have markedly low blood volume (up to 1,000 mL below normal) alongside paradoxically suppressed renin and aldosterone — the inverse of normal physiology in response to hypovolemia. The mechanism for this paradox remains unresolved (Streeten and Bell 2001).
Microvascular remodelling. Reduced capillary density and thickened capillary basement membranes in skeletal muscle (capillary BM thickening independently replicated in 3 countries: Amsterdam (Charlton et al. 2025), Berlin (Aschman et al. 2023), Aarhus (Agergaard et al. 2023)); CD169⁺ macrophage infiltration after exercise; endothelial microvacuolization, hypertrophy, and degeneration on EM (Charlton et al. 2025); reduced capillary tortuosity and contact length reduce total O₂ exchange surface area; direct 60-day bed rest comparator excluded deconditioning as the sole explanation. Tissue O₂ uptake and vasodilatory capacity both impaired (NIRS) (Charlton et al. 2025) (Joseph et al. 2022).
Full discussion: Cardiovascular Dysfunction.
Evidence status: Established (hypoperfusion and endothelial dysfunction independently replicated; RAAS paradox well-documented).