Greater inflammation in women with hypertensive disorders of pregnancy may relate to angiogenic dysregulation

Background: Hypertensive disorders of pregnancy (HDP) are marked by excessive inflammatory responses and dysregulation of angiogenic factors that contribute to maladaptive placentation. While studies have investigated inflammation or angiogenic factors in HDP, few have included longitudinal and broad simultaneous assessment of these biomarkers. Thus, we studied the hypothesis that women who developed an HDP would express a greater pro-inflammatory profile and dysregulation of angiogenic factors from early-to-late gestation, whereby these outcomes would be related. Methods: Eleven women with normal pregnancies (NORM; age: 30±6 y; body mass index [BMI]: 27.3±7.6 kg/m 2 ) and 9 women who developed HDP (age: 32±4 y; BMI: 27.7±5.3 kg/m 2 ) were studied during early (4-12 weeks) and late (30-34 weeks) gestation. Serum and plasma samples were taken at each visit. Pro-angiogenic (placental growth factor [PlGF]) and anti-angiogenic (soluble endoglin [sENG], soluble fms-like tyrosine kinase-1 [sFlt-1]) factors were measured using ELISA. Corin, an enzyme indirectly affecting vascular remodeling, was also measured via ELISA. Pro-inflammatory (IFN-γ, IL-1β, IL-2, IL-6, IL-8, IL-12p70, IL-17A, IP-10, MCP-1, and TNF-α) and anti-inflammatory (IL-4, IL-10) cytokines were measured using a multiplex bead-based immunoassay. Cytokine data are reported as geometric mean ± geometric SD factor, while all other data are arithmetic mean ± SD. Results: Regarding pro-angiogenic factors, PlGF increased from early-to-late pregnancy (NORM: 37.4±35.0 to 294.2±252.2 pg/mL; HDP: 30.1±14.7 to 166.5±14.3 pg/mL; time P < 0.001). For anti-angiogenic factors, sENG increased from early-to-late pregnancy (NORM: 4.87±1.07 to 6.30±3.18 ng/mL; HDP: 6.32±1.17 to 10.07±3.05 ng/mL; time P < 0.001), was greater in HDP (group P = 0.006), and trended towards an interaction (P = 0.086). sFlt-1 tended to increase across pregnancy (NORM: 7135±2891 to 10468±10588 pg/mL; HDP: 7282±2620 to 11928±7429 pg/mL; time P = 0.051). Further, corin increased while sFlt-1:PlGF ratio decreased across pregnancy (both P ≤ 0.002), with corin trending towards an interaction (P = 0.083). Regarding pro-inflammatory cytokines, HDP expressed lower IL-2 (P = 0.004; group effect) and interactions were noted for IL-8 and MCP-1 (both P ≤ 0.037). Both cytokine concentrations decreased across pregnancy in NORM (IL-8: 9.16±7.10 to 4.99±6.90 pg/mL; MCP-1: 90.08±2.24 to 53.32±1.97 pg/mL; both P ≤ 0.002) but not in HDP (IL-8: 13.24±8.08 to 12.43±7.38 pg/mL; MCP-1: 115.34±2.48 to 120.82±2.63 pg/mL; both P ≥ 0.766). For anti-inflammatory cytokines, an interaction was noted for IL-4 (P = 0.022) with a reduction from early-to-late in NORM (5.96±1.63 to 4.13±1.84 pg/mL; P = 0.030), but not HDP (4.88±4.54 to 6.36±5.45 pg/mL; P = 0.184). No other interactions were noted for other cytokines (P range: 0.146-0.759). The early-to-late change (Δ) in sFlt-1 related to ΔIL-17A (r = 0.535; P = 0.033), ΔIL-10 (r = 0.506; P = 0.046), and ΔIL-12p70 (r = 0.632; P = 0.012). Additionally, Δcorin related to ΔIP-10 (r = 0.719; P = 0.013) and ΔsFlt-1:PlGF ratio correlated with ΔIL-6 (r = 0.744; P = 0.004). Conclusions: Our findings demonstrate that the inflammatory profile changes exhibited in women during normal pregnancy are not mirrored in women who develop HDP. Importantly, while we did not observe significant group-by-time interactions in angiogenic factors, several inflammatory cytokines were moderately-to-strongly correlated with these biomarkers. Taken together, these preliminary data suggest that dysregulation of the angiogenic factors promoting proper placentation may contribute to a greater late pregnancy inflammatory load and the development of HDP. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.