Comorbid hypertension and osteoarthritis exacerbates joint remodeling and gait compensations in female rats with milder effects observed in males.

OBJECTIVE: Osteoarthritis (OA) often presents with comorbidities such as hypertension, potentially accelerating OA pathogenesis. We hypothesized that hypertension would exacerbate joint-level pathogenesis and OA-related symptoms in a sex-dependent manner. METHODS: Male and female Spontaneously Hypertensive rats (hypertensive) and Sprague Dawley rats (normotensive) underwent either medial collateral ligament and medial meniscus transection (OA) or skin incision (sham) in the right knee (N ​= ​80; n ​= ​10/group/sex). Symptoms were measured monthly (gait) and bi-weekly (tactile sensitivity) for 8 weeks. Endpoint histology assessed joint-level damage, neurovascular changes, and cytokine levels in synovial fluid. RESULTS: At endpoint, hypertensive-OA rats had thinner cartilage across the medial tibial plateau than normotensive-OA rats (non-overlapping 95 ​% CI), regardless of sex. While not observed in males, hypertensive-OA females developed larger osteophytes (Q1-Q3 ​= ​0.049-0.124 ​mm(2)) than normotensive-OA females (Q1-Q3 ​= ​0.026-0.047 ​mm(2), p ​= ​0.02) and ranked higher for CD31(+) vasculature in the subchondral bone plate (Q1-Q3 ​= ​18.2-21.5) than normotensive-OA females (Q1-Q3 ​= ​1; p ​= ​0.01). Hypertensive-OA females developed a limping gait, shifting stance times from their OA to non-OA limb (stance time imbalance ​= ​1.20 ​± ​1.15 ​%, p ​= ​0.04), offloaded their injured limb quicker (temporal symmetry ​= ​52.5 ​± ​1.4 ​%, p ​< ​0.001), and reduced stride lengths (weeks 4 and 8; hypertensive-OA ​< ​normotensive-OA, p ​< ​0.001). These gait changes were not observed in normotensive-OA females or males, nor in hypertensive-OA males. CONCLUSIONS: Hypertension worsened OA pathogenesis at the joint level, more substantially affecting joint remodeling and gait compensations in females. Our results encourage further investigation into the pathophysiologic drivers linking hypertension and OA, particularly vascular changes and sex differences.