Dietary Sodium-Regulated Plasma SVEP1 and Inverse Salt Sensitivity

Although some individuals exhibit salt sensitivity, others demonstrate salt resistance or inverse salt sensitivity-blood pressure reduction during a high-sodium diet. The molecular mechanisms underlying heterogeneous blood pressure responses to dietary sodium remain poorly understood.

We conducted a randomized crossover trial in 20 adults (blood pressure <140/90 mm Hg), comparing 8-day low-sodium (10 mmol/d) versus high-sodium (300 mmol/d) diets. Plasma proteomics used SomaLogic's 7K v4.1 platform (≈7000 proteins). Protein changes between diets were compared with blood pressure changes.

Despite higher weight (+1.4 kg) during high-sodium diet (P=1.08×10^-5), diastolic blood pressure (67.0±7.5 versus 69.7±8.0 mm Hg, P=0.009), and mean arterial pressure (82.1±7.6 versus 84.8±8.3 mm Hg; P=0.006) were significantly lower. Thus, our participants exhibited inverse salt sensitivity. In body mass index-adjusted models, 2 independent aptamers targeting SVEP1 (sushi, von Willebrand Factor type A, EGF [Epidermal Growth Factor], and pentraxin domain-containing 1) ranked second (Benjamini-Hochberg-adjusted; P=7.08×10^-5) and sixth (Benjamini-Hochberg-adjusted P=4.42×10^-3) among all measurements, outranking established sodium-regulatory hormones including renin (14th) and NT-proBNP (N-terminal pro-B-type natriuretic peptide; 25th). SVEP1 upregulation correlated inversely with blood pressure changes (R=-0.51; P=0.026). SVEP1 changes correlated strongly with NT-proBNP (R=0.80, P<0.001). Reactome analysis revealed coordinated extracellular matrix remodeling as the dominant biological response to sodium loading.

SVEP1 emerges as a key molecular correlate of blood pressure responses to dietary sodium, likely through a volume- or stretch-mediated stimulus. Given SVEP1's established functions in vascular smooth muscle relaxation and lymphangiogenesis, these findings suggest novel pathways mediating cardiovascular adaptation to sodium challenges and potential biomarkers for identifying salt-sensitive versus salt-resistant individuals.