Increased blood flow and tendon swelling precedes vascular expansion and tissue matrix changes in early human tendinopathy

Key points

1. 01Tendon blood flow (Doppler) was elevated in both early and chronic tendinopathy, but vascular expansion (CD31, ANGPTL4, VCAM1) was significant only in the chronic group, suggesting early hyperperfusion reflects dilation of existing vessels rather than new vessel growth.
2. 027T MRI detected tendon swelling in early tendinopathy that 3T MRI missed, and tendon size correlated significantly with pain scores and symptom duration.
3. 03Most extracellular matrix protein changes (matrisome) appeared only in chronic tendinopathy; only 1 of 229 matrisome proteins differed significantly in early versus healthy tendons.
4. 04Cell DIVE imaging identified perivascular recruitment of CD90+ fibroblasts and macrophages, plus potential lymphatic vessel expansion, predominantly in tendinopathic samples.
5. 05In the clinical recovery cohort, patients treated within 1 month improved by 34% on the VISA-A at 12 weeks versus 12% for the 2-3 month group (p significant vs 2-3 month group).

How it was conducted

Design

Cross-sectional with three groups plus a separate retrospective clinical cohort

Participants

14 early tendinopathy (ET, symptoms <3 months), 16 chronic tendinopathy (CT, >3 months), 15 healthy controls (CTRL); ages 21-43 years

Primary condition

Patellar tendinopathy; clinical recovery analysis used 69 Achilles tendinopathy patients

Imaging

3T and 7T MRI for tendon volume and cross-sectional area; ultrasound power-Doppler for blood flow

Tissue analysis

Patellar tendon biopsies analyzed by immunofluorescence, Cell DIVE multiplex imaging, and LC-MS/MS proteomics (2615 proteins identified)

Primary outcome

Sequence of vascular, structural, and matrix changes across tendinopathy stages; correlation with pain and function (VISA-P, SLDS)

What they found

• Patellar tendon thickness (mean +/- SD): CTRL 4.57 +/- 0.66 mm, ET 5.56 +/- 1.76 mm, CT 7.97 +/- 1.58 mm (p < 0.0001).
• Doppler blood flow was significantly increased in ET and CT versus CTRL, with a further increase from ET to CT; peritendinous blood flow increased only in CT versus CTRL and ET.
• Microscopic vascularity (CD31) correlated with Doppler blood flow (r = 0.47, p < 0.01 including asymptomatic tendons; r = 0.34, p < 0.01 excluding asymptomatic tendons).
• Vascular protein ANGPTL4 staining area differed significantly between groups (p < 0.05); trends seen for CD31 (p = 0.06), VCAM1 (p = 0.09), VEGF (p = 0.06); significant vascular differences were confined to CT in post-hoc comparisons.
• Of 2615 proteins: 247 differed CT vs CTRL, 125 differed ET vs CTRL, and only 6 differed ET vs CT.
• Matrisome proteins: 229 total identified; 12 differed CT vs CTRL, only 1 differed ET vs CTRL, and 0 differed ET vs CT.
• Vascular GO-term proteins: 11 differed CT vs CTRL, 5 differed ET vs CTRL, 1 differed ET vs CT.
• Clinical cohort VISA-A improvement at 12 weeks: <1 month symptom duration 34 +/- 3% vs 2-3 months 12 +/- 2% (significantly higher, p reported as significant).
• 7T MRI showed borderline higher normalized proximal CSA/mass in ET vs CTRL (p = 0.03 for group including contralateral tendons); 3T MRI did not detect ET vs CTRL differences.

Limitations

• Cross-sectional design cannot establish within-subject temporal progression; a prospective longitudinal design with repeated biopsies is not feasible because biopsy itself upregulates tendon cell activity.
• Classifying early tendinopathy by symptom duration introduces recall bias and the 90-day cutoff is based on convention, not a validated biological threshold.
• Inclusion requiring tendon thickening or Doppler signal may have biased the early tendinopathy group toward participants with more pronounced tissue changes.
• Cell DIVE analysis used a small subset of samples, precluding statistical testing for vessel phenotype findings; the CT group had large symptom duration heterogeneity (102-3670 days).

Why it matters

For patients

People who develop tendon pain should seek assessment and treatment early, as recovery appears faster when treatment begins within 1 month of symptom onset compared with waiting 2-3 months.

For clinicians

Early tendinopathy is characterized by hyperperfusion and swelling in structurally intact vessels rather than new vessel growth or matrix degradation, suggesting that interventions targeting fluid accumulation or vasodilation (such as hyaluronidase or nitric oxide donors) may be most effective before the chronic structural phase sets in.

For readers

This paper maps the biological sequence of tendinopathy for the first time using multi-modal human data, identifying an early reversible phase that could be a therapeutic window before irreversible angiogenesis and matrix remodeling occur.