Real-World Safety Outcomes with Brolucizumab in Neovascular Age-Related Macular Degeneration: Findings from the IRIS® Registry.

INTRODUCTION: To assess real-world safety outcomes for adults with neovascular age-related macular degeneration (nAMD) treated with brolucizumab from the US-based IRIS® (Intelligent Research in Sight) Registry. METHODS: In this retrospective study, 18,312 eyes (15,998 patients) treated with ≥ 1 intravitreal brolucizumab injections between 8 October 2019 (US launch date for brolucizumab) and 7 October 2021 were followed up for ≤ 2 years after first injection (index date). The study assessed the predefined incident ocular adverse events of intraocular inflammation (IOI), retinal vasculitis (RV), and retinal vascular occlusion (RO). RESULTS: Overall, 614/18,312 eyes (3.4%) experienced any IOI, RV, and/or RO event. Median (interquartile range [IQR]) time to an event was 84 (42-167) days; 77.4% of events (475/614) occurred within 6 months after index date. Median (IQR) number of brolucizumab injections before an event was 2 (1-4). For eyes with an adverse event and visual acuity (VA) data (n = 406), median (IQR) change in Early Treatment of Diabetic Retinopathy Study (ETDRS) letters from pre-event VA was 0 (- 7 to + 5) at the 6-month follow-up; 50 eyes (12.3%) had a VA loss of 10 or more ETDRS letters. Risk of an event (hazard ratio [95% confidence interval]) was decreased in eyes from male patients (0.61 [0.53-0.71]), from older patients (0.83 [0.76-0.90]), from treatment-naive patients (0.51 [0.38-0.69]), and from patients who started brolucizumab in the second year after launch (0.68 [0.53-0.86] vs. first year). CONCLUSION: In this large real-world brolucizumab safety study, 3.4% of eyes experienced an IOI, RV, and/or RO event. Among eyes that experienced an adverse event for which VA data were available, median ETDRS vision change was 0 letters (IQR - 7 to + 5).

One-Year Brolucizumab Outcomes in Neovascular Age-Related Macular Degeneration from a Large United States Cohort in the IRIS® Registry.

PURPOSE: To evaluate visual acuity (VA) and injection intervals in patients with neovascular age-related macular degeneration (nAMD) after 12 months of brolucizumab therapy in clinical practice. DESIGN: Retrospective cohort study. PARTICIPANTS: Adults in the United States-based IRIS® Registry (Intelligent Research in Sight) with nAMD who received brolucizumab exclusively for 12 months (2308 eyes of 2079 patients). METHODS: Observational study of eyes with a first injection of brolucizumab (index), followed by 2 or more brolucizumab injections over the following 12 months without switching to another anti-vascular endothelial growth factor (VEGF) agent. MAIN OUTCOME MEASURES: Primary outcomes were change in best recorded VA and, for eyes receiving prior anti-VEGF therapy (treatment-experienced eyes), the difference between the brolucizumab injection interval at 12 months and the anti-VEGF injection interval before switching. The interval before switching was defined as the time between the prior anti-VEGF and index brolucizumab injections; brolucizumab interval was the time between the closest injection to day 365 and the preceding injection. Secondary outcomes included incident adverse events. RESULTS: Overall VA at index was 61.6 ± 18.4 Early Treatment Diabetic Retinopathy Study letters; 83.7% of treatment-naive eyes (184/220) and 86.1% of treatment-experienced eyes (1797/2088) showed stable (< 10 letters gained or lost) or improved (≥ 10 letters gained) VA at 12 months. Among treatment-experienced eyes receiving a prior anti-VEGF injection within 365 days before index, 29.5% (594/2015) showed an interval before switching of 8 weeks or more (mean, 7.6 ± 5.5 weeks), whereas 83.1% (1734/2015) showed a brolucizumab injection interval at 12 months of 8 weeks or more (mean, 10.3 ± 4.0 weeks). In all, 77.1% of treatment-experienced eyes (1554/2015) showed an interval extension of 1 week or more; of these, 55.4% (861/1554) showed an extension of 4 weeks or more. CONCLUSIONS: In this community-based study, at 12 months, brolucizumab treatment prolonged the interval between anti-VEGF injections for most treatment-experienced eyes, particularly those with shorter intervals before switching, while maintaining or improving VA. With careful balancing of the benefits and risks, switching to brolucizumab treatment may offer the advantage of extending the treatment interval for patients with a high anti-VEGF therapy burden. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Factors Linked to Injection Interval Extension in Eyes with Wet Age-Related Macular Degeneration Switched to Brolucizumab.

PURPOSE: To evaluate factors associated with anti-vascular endothelial growth factor (VEGF) injection interval extension in patients with neovascular age-related macular degeneration (nAMD) switched to brolucizumab treatment. DESIGN: Retrospective, observational cohort study. PARTICIPANTS: Adults in the United States-based IRIS® Registry (Intelligent Research in Sight) with nAMD who switched from another anti-VEGF agent to brolucizumab-only treatment for ≥ 12 months from October 8, 2019, through November 26, 2021. METHODS: Univariable and multivariable analyses examined associations of demographic and clinical characteristics with the likelihood of interval extension after switching to brolucizumab therapy. MAIN OUTCOME MEASURES: Eyes were classified as either extenders or nonextenders at 12 months. Extenders were eyes that achieved (1) an extension of ≥ 2 weeks in the brolucizumab injection interval at 12 months versus the interval before switching (time between the last known prior anti-VEGF injection and first [index] brolucizumab injection) and (2) stable (< 10 letters gained or lost) or improved (≥ 10 letters gained) visual acuity (VA) at 12 months versus VA at index injection. RESULTS: Of 2015 eyes among 1890 patients who switched to brolucizumab treatment, 1186 (58.9%) were extenders. In univariable analyses, demographic and clinical characteristics were comparable between extenders and nonextenders, except that extenders had shorter intervals before switching versus nonextenders (mean, 5.9 ± 2.1 weeks vs. 10.1 ± 7.6 weeks, respectively). In multivariable logistic regression modeling, a shorter interval before switching was associated significantly and positively with interval extension with brolucizumab therapy (adjusted odds ratio, 5.6 for interval before switching of < 8 weeks versus ≥ 8 weeks; 95% confidence interval, 4.5-6.9; P < 0.001), and eyes with an index VA of 40 to 65 letters were significantly less likely to be extenders than eyes in the higher (better) index VA categories. CONCLUSIONS: Length of the treatment interval before switching was the characteristic associated most strongly with successful interval extension with brolucizumab. Treatment-experienced patients who required more frequent injections (i.e., shorter intervals before switching) showed the greatest extensions when switching to brolucizumab. With careful consideration of benefits and risks, brolucizumab may be a valuable option for patients with higher treatment burdens because of the need for frequent injections. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references.

Does Adjunctive Under-flap CXL Reduce Regression for Hyperopic LASIK?

PURPOSE: To investigate whether adding accelerated under-flap corneal cross-linking to hyperopic laser in situ keratomileusis (LASIK-ufCXL) affects postoperative stability and regression, visual and refractive outcomes, and subjective quality of vision. METHODS: This prospective comparative contralateral eye study included 51 patients with hyperopia (102 eyes) who received LASIK-ufCXL in the eye with highest defocus equivalent (DEQ) or randomized when DEQ equal, with the contralateral control eye receiving LASIK alone. After excimer ablation, 0.25% riboflavin was instilled on the stromal bed for 3 minutes. The flap was repositioned, followed by a total irradiation dose of 3.24 J ultraviolet A (UV-A) light administered to the corneal surface, using 18 mW/cm2 UV-A for 3 minutes. Postoperative hyperopic regression (stability) was the primary outcome measure, defined by the difference in spherical equivalent (SEQ) at 1 week and 24 months postoperatively. Secondary measures reported uncorrected distance visual acuity, corrected distance visual acuity, cylinder vector analysis, subjective quality of vision, subjective night vision disturbances, and corneal haze. RESULTS: At 24 months, the SEQ stability (P = .4273) and the magnitude of hyperopic regression (P = .5613) did not significantly differ between groups, with a small trend showing hyper-opic regression of 0.50 diopters or greater being less frequent in LASIK-ufCXL eyes. There were no significant differences in accuracy, efficacy, and safety (P > .05), with a small trend of more residual refractive astigmatism in the LASIK-ufCXL group (P = .3216, Cohen's d: -0.29). Subjective quality of vision trended inferior in LASIK-ufCXL eyes (P = .2237, Cohen's d: -0.25), with a greater haze grading (P = .0466, Cohen's d: 0.41). CONCLUSIONS: Postoperative regression and stability were statistically equivalent between hyperopic LASIK vs LASIK-ufCXL, with identical safety. There were small clinical trends of lower efficacy, accuracy, and subjective quality of vision in LASIK-ufCXL eyes. [J Refract Surg. 2022;38(12):770-779.].

MERLIN: Phase 3a, Multicenter, Randomized, Double-Masked Trial of Brolucizumab in Participants with Neovascular Age-Related Macular Degeneration and Persistent Retinal Fluid.

PURPOSE: To assess the 52-week efficacy and safety of brolucizumab 6 mg administered every 4 weeks compared with aflibercept 2 mg dosed every 4 weeks in eyes with neovascular age-related macular degeneration (nAMD) and persistent retinal fluid. DESIGN: Multicenter, randomized, double-masked phase 3a study. PARTICIPANTS: Participants with recalcitrant nAMD (persistent residual retinal fluid despite previous frequent anti-vascular endothelial growth factor treatment). METHODS: Eyes were randomized (2:1) to intravitreal brolucizumab 6 mg or aflibercept 2 mg every 4 weeks up to and including week 100. MAIN OUTCOME MEASURES: The primary end point was analysis of noninferiority in mean best-corrected visual acuity (BCVA) change from baseline to week 52 (margin, 4 letters). Other key end points included change in central subfield thickness (CST) from baseline to week 52, fluid-free status (no intraretinal fluid and no subretinal fluid), and safety. RESULTS: At week 52, brolucizumab was noninferior to aflibercept in BCVA change from baseline (least squares mean difference, -0.6 Early Treatment Diabetic Retinopathy Study letters; 95% confidence interval [CI], -2.1 to 0.9; P < 0.001). A total of 4.8% and 1.7% of participants reported a 15-letter or more BCVA loss from baseline at week 52 in the brolucizumab and aflibercept groups, respectively. In eyes treated with brolucizumab compared with those treated with aflibercept, the CST was reduced significantly (P < 0.001), and a significantly greater proportion of eyes were fluid free at week 52 (40.4% brolucizumab vs. 19.0% aflibercept; 95% CI, 13.9-29.0; P < 0.001). Incidence of intraocular inflammation (IOI), including retinal vasculitis and retinal vascular occlusion, were 9.3% (0.8% and 2.0%) for brolucizumab versus 4.5% (0% and 0%) for aflibercept, respectively. CONCLUSIONS: Visual acuity outcomes in previously treated participants with nAMD and persistent retinal fluid receiving brolucizumab 6 mg dosed every 4 weeks were noninferior to aflibercept 2 mg dosed every 4 weeks, with superior anatomic outcomes. However, incidences of IOI, including retinal vasculitis and retinal vascular occlusion, also were higher, leading to study termination.

Refractive, visual, and subjective quality of vision outcomes for very high myopia LASIK from - 10.00 to - 13.50 diopters.

BACKGROUND: To evaluate laser-assisted in situ keratomileusis (LASIK) outcomes, subjective quality of vision (QoV) and patient satisfaction in eyes with very high myopia (VHM) above - 10.00 diopters (D). METHODS: Consecutive myopic and myopic-astigmatism eyes with spherical equivalent (SEQ) ranging between - 10.00 to - 13.50 D underwent LASIK with the WaveLight® Allegretto Wave® Eye-Q 400 Hz excimer laser. Treatment accuracy, efficacy, safety, stability, cylinder vectors, and higher-order aberrations were evaluated, together with subjective QoV and night vision disturbances (NVDs). RESULTS: 114 eyes had a preoperative SEQ of - 11.02 ± 0.81 D, with a median follow-up of 24 months. A total of 72, 84, and 94% of eyes were within ± 0.50, ± 0.75 and ± 1.00 D of intended SEQ (R2 = 0.71). The efficacy index was 0.93 ± 0.20, with 51 and 81% of eyes achieving 20/20 and 20/25. The astigmatism correction index was 0.95 ± 0.33. The safety index was 1.05 ± 0.12. The average myopic regression was - 0.51 ± 0.38 D. Preoperative QoV scores improved significantly postoperatively (7.5 ± 0.8 vs. 9.1 ± 0.7; P <  0.001), with less NVDs (P <  0.001). Total, spherical and coma root mean square (RMS) postoperative ocular higher-order aberrations were 1.07 ± 0.34, 0.67 ± 0.25, and 0.70 ± 0.40 µm. CONCLUSIONS: Very high myopia LASIK between - 10.00 to - 13.50 D is safe and results in good visual outcomes, with high patient satisfaction and a significant improvement in patient-reported QoV after surgery. Appropriately selected patients within this very high myopia group can be included as LASIK candidates.

Primary Topography-Guided LASIK: Refractive, Visual, and Subjective Quality of Vision Outcomes for Astigmatism ⩾2.00 Diopters.

PURPOSE: To evaluate the outcomes of primary topography-guided laser in situ keratomileusis (LASIK) in eyes with subjective refractive astigmatism of 2.00 diopters (D) or greater. METHODS: This was a prospective study in consecutive eyes with cylinder of 2.00 D or greater that had LASIK using the Alcon WaveLight EX500 excimer laser and T-CAT/Contoura software (Alcon Laboratories, Inc., Fort Worth, TX). The accuracy, efficacy, safety, cylinder vector analysis, higher order aberrations, and patients' subjective quality of vision were assessed. Eyes with naturally occurring topographic irregular astigmatism were not excluded. RESULTS: The mean cylinder was -2.55 D preoperatively and -0.34 D postoperatively; 81% and 95% of eyes were within ±0.50 and ±0.75 D of intended cylinder after LASIK, respectively. The correction index and index of success were 1.00 and 0.13, respectively. The efficacy and safety indexes were 0.98 and 1.04, respectively. The preoperative corneal topography irregularity index, anterior corneal higher order aberrations, and refractive astigmatism magnitude were mildly correlated to postoperative residual astigmatism. Mean ocular and corneal coma were not increased postoperatively. Patients had significant improvements after LASIK in both subjective uncorrected quality of vision and night vision disturbances compared to spectacle- and contact lens-corrected vision before LASIK. CONCLUSIONS: Topography-guided ablation using the Alcon WaveLight EX500 excimer laser and T-CAT/Contoura software results in excellent accuracy, efficacy, and safety, with improved postoperative subjective quality of vision and reduced night vision disturbances in virgin eyes with refractive astigmatism of 2.00 D or greater, including eyes with topographic naturally occurring irregular astigmatism. [J Refract Surg. 2019;35(2):78-86.].

Clinically significant laser in situ keratomileusis flap striae.

PURPOSE: To describe the incidence, risk factors, and outcomes before and after irrigation of clinically significant laser in situ keratomileusis (LASIK) flap striae. SETTING: Multisurgeon multicenter standardized protocol practice. DESIGN: Retrospective case-control series. METHODS: Eyes with striae necessitating flap relift and irrigation were identified. Preoperative, intraoperative, and postoperative variables were collected. Incidence, risk factors, and outcomes were assessed. RESULTS: Of the 109 403 eyes that had LASIK, the incidence of striae-treated eyes was 0.79% (n = 875), with 8.7% irrigated the first hour after surgery. The preoperative spherical equivalent (SE) and ablation depth exponentially increased the striae risk (R2 = 0.9674; P < .001). Striae induced a small hyperopic shift that reversed after the relift (mean 0.22 diopter [D] ± 0.52 [SD] versus -0.02 ± 0.45 D) (P < .001). After relifting, 68.0%, 87.0%, and 96.0% of eyes had an uncorrected distance visual acuity (UDVA) of 20/20, 20/25, 20/40 or better versus 25.0%, 55.0%, and 84.0%, respectively, before the relift (P < .001). Thirteen percent fewer striae-treated eyes achieved a UDVA of 20/20. Before relifting, 51.0% of striae eyes lost 1 or more lines of corrected distance visual acuity, with a safety index reverting to control values (0.99 versus 1.00) (P > .05) after the relift. A laser refractive enhancement was performed in 6.28% of relifted striae eyes versus 3.04% in nonstriae control eyes. CONCLUSIONS: Flap striae requiring surgeon intervention occurred in 0.79% of eyes. Higher preoperative SE values were associated with an exponential increase risk for striae. Treatment by lifting and irrigation significantly improved the accuracy, efficacy, and safety to a level close to that of contralateral control eyes, although striae-treated eyes were more likely to need excimer laser retreatment.

Under-flap stromal bed CXL for early post-LASIK ectasia: a novel treatment technique.

PURPOSE: Collagen cross-linking (CXL) for post-laser-assisted in situ keratomileusis (LASIK) ectasia (PLE) is traditionally performed either epi-on or epi-off on the corneal surface. This study describes a novel technique in treating early PLE with under-flap CXL (ufCXL) to the stromal bed and reports on 6-month outcomes. PATIENTS AND METHODS: Case series of seven patients (eight eyes) with topography-diagnosed early PLE treated with ufCXL. Inclusion criteria were early, mild PLE defined as new-onset postoperative manifest refraction cylinder ≤1.50 D, with new topographic inferior steepening consistent with ectasia, uncorrected distance visual acuity (UDVA) of 20/40 or better, and corrected distance visual acuity (CDVA) of 20/25 or better. Existing LASIK flap was lifted, riboflavin was applied directly to the stromal bed, flap was repositioned, and 18 mW/cm2 ultraviolet light was applied for 3 minutes to the corneal surface. Post-ufCXL manifest refraction, UDVA and CDVA, corneal cylinder, Kmax, and corneal irregularity index were compared with pre-ufCXL measurements. RESULTS: Patients had a pre-ufCXL sphere of 0.09±0.48 D and cylinder of -0.78±0.49 D. At 6 months, post-ufCXL sphere (0.06±0.8 D; P=0.89) and cylinder (-1.09±0.76 D, P=0.26) were unchanged. Cumulative post-ufCXL UDVA was unchanged, achieving 20/20, 20/30, and 20/40 in 25%, 88%, and 88%, respectively, compared with 13%, 63%, and 88% pre-ufCXL (P=0.68). Post-ufCXL CDVA was unchanged (P=0.93) with a gain of one line in two eyes, a loss of one line in one eye, and five eyes unchanged. The efficacy index (P=0.76), safety index (P=0.89), Kmax (P=0.94), and corneal irregularity index (P=0.73) were also unchanged. CONCLUSION: Preliminary results with ufCXL for early PLE are promising, demonstrating maintenance of visual accuracy, efficacy, safety, Kmax, and cylinder, with much quicker recovery times than surface CXL.

Type VIII collagen mediates vessel wall remodeling after arterial injury and fibrous cap formation in atherosclerosis.

Collagens in the atherosclerotic plaque signal regulation of cell behavior and provide tensile strength to the fibrous cap. Type VIII collagen, a short-chain collagen, is up-regulated in atherosclerosis; however, little is known about its functions in vivo. We studied the response to arterial injury and the development of atherosclerosis in type VIII collagen knockout mice (Col8(-/-) mice). After wire injury of the femoral artery, Col8(-/-) mice had decreased vessel wall thickening and outward remodeling when compared with Col8(+/+) mice. We discovered that apolipoprotein E (ApoE) is an endogenous repressor of the Col8a1 chain, and, therefore, in ApoE knockout mice, type VIII collagen was up-regulated. Deficiency of type VIII collagen in ApoE(-/-) mice (Col8(-/-);ApoE(-/-)) resulted in development of plaques with thin fibrous caps because of decreased smooth muscle cell migration and proliferation and reduced accumulation of fibrillar type I collagen. In contrast, macrophage accumulation was not affected, and the plaques had large lipid-rich necrotic cores. We conclude that in atherosclerosis, type VIII collagen is up-regulated in the absence of ApoE and functions to increase smooth muscle cell proliferation and migration. This is an important mechanism for formation of a thick fibrous cap to protect the atherosclerotic plaque from rupture.

Type VIII collagen signals via ß1 integrin and RhoA to regulate MMP-2 expression and smooth muscle cell migration.

The extracellular matrix signals and regulates the behavior of vascular cells during the pathogenesis of atherosclerosis. Type VIII collagen, a short chain collagen, is scarcely present in normal arteries, but is dramatically upregulated in atherosclerosis and after other types of vascular injury. Cell culture studies have revealed that this protein supports smooth muscle cell (SMC) adhesion and stimulates migration, however little is known about the signaling or the mechanisms by which this occurs. SMCs isolated from wild-type C57BL/6 and type VIII collagen deficient mice were studied using assays to measure chemotactic and haptotactic migration, and remodeling and contraction of 3-dimensional type I collagen gels. Col8(-/-) SMCs exhibited impairments in migration, and a strongly adhesive phenotype with prominent stress fibers, stable microtubules and pronounced central basal focal adhesions. The addition of exogenous type VIII collagen to the Col8(-/-) SMCs rescued the impairments in migration, and restored cytoskeletal architecture so that it was similar to Col8(+/+) cells. We measured elevated levels of active GTP-RhoA in the Col8(-/-) cells, and this too was reversed by treatment with exogenous type VIII collagen. We showed that type VIII collagen normally suppresses RhoA activation through a beta-1 integrin dependent mechanism. MMP-2 levels were reduced in the Col8(-/-) SMCs, and knockdown of MMP-2 in Col8(+/+) SMCs partially recapitulated the decreases in migration and 3D gel contraction seen in Col8(-/-) cells, showing that type VIII collagen-stimulated migration was dependent on MMP-2. Inhibition of Rho restored MMP-2 activity in the Col8(-/-) cells, and partially rescued migration, demonstrating that the elevations in RhoA activity were responsible for the suppression of migration of these cells. In conclusion, we have shown that type VIII collagen signals through beta-1 integrin receptors to suppress RhoA, allowing optimal configuration of the cytoskeleton, and the stimulation of MMP-2-dependent cell migration.

Collagens in the progression and complications of atherosclerosis.

Collagens constitute a major portion of the extracellular matrix in the atherosclerotic plaque, where they contribute to the strength and integrity of the fibrous cap, and also modulate cellular responses via specific receptors and signaling pathways. This review focuses on the diverse roles that collagens play in atherosclerosis; regulating the infiltration and differentiation of smooth muscle cells and macrophages; controlling matrix remodeling through feedback signaling to proteinases; and influencing the development of atherosclerotic complications such as plaque rupture, aneurysm formation and calcification. Expanding our understanding of the pathways involved in cell-matrix interactions will provide new therapeutic targets and strategies for the diagnosis and treatment of atherosclerosis.

Oxidized phospholipids induce type VIII collagen expression and vascular smooth muscle cell migration.

Phenotypic switching of vascular smooth muscle cells (VSMCs) is known to play a critical role in the development of atherosclerosis. However, the factors present within lesions that mediate VSMC phenotypic switching are unclear. Oxidized phospholipids (OxPLs), including 1-palmitoyl-2-(5-oxovaleroyl)-sn-glycero-3-phosphorylcholine (POVPC), are active components of minimally modified low density lipoprotein and have been previously shown to induce multiple proatherogenic events in endothelial cells and macrophages, but their effects on VSMCs have been largely unexplored until recently. We previously showed that OxPLs induced phenotypic switching of VSMCs, including suppression of SMC differentiation marker genes. The goal of the present studies was to test the hypothesis that OxPLs alter extracellular matrix production and VSMC migration. Results showed that POVPC activated expression of several extracellular matrix proteins in VSMC. POVPC increased expression of type VIII collagen alpha1 chain (Col8a1) mRNA in cultured VSMCs and in vivo in rat carotid arteries by 9-fold and 4-fold, respectively. POVPC-induced activation of Col8a1 gene expression was reduced by small interfering RNA-mediated suppression of Krüppel-like factor 4 (Klf4) and Sp1, and was abolished in Klf4-knockout VSMCs. POVPC increased Klf4 binding to the Col8a1 gene promoter both in vivo in rat carotid arteries and in cultured VSMCs based on chromatin immunoprecipitation assays. Moreover, POVPC-induced VSMC migration was markedly reduced in Klf4- or type VIII collagen-knockout VSMCs. Given evidence that OxPLs are present within atherosclerotic lesions, it is interesting to suggest that OxPL-induced changes in VSMC phenotype may contribute to the pathogenesis of atherosclerosis at least in part through changes in extracellular matrix composition.

Migration and growth are attenuated in vascular smooth muscle cells with type VIII collagen-null alleles.

OBJECTIVE: Type VIII collagen is upregulated after vascular injury and in atherosclerosis. However, the role of type VIII collagen endogenously expressed by smooth muscle cells (SMCs) and in the context of the vascular matrix microenvironment, which is rich in type I collagen, is not known. To address this, we have compared aortic SMCs from wild-type (WT) mice to SMCs from type VIII collagen-deficient (KO) mice when plated on type I collagen. METHODS AND RESULTS: Type VIII collagen was upregulated after wounding of WT SMCs. KO SMCs exhibited greater adhesion to type I collagen than WT SMCs (optical density [OD595]=0.458+/-0.044 versus 0.193+/-0.071). By contrast, the WT SMCs spread more (389+/-75% versus 108+/-14% increase in cell area), migrated further (total distance 80.6+/-6.2 microm versus 64.2+/-4.4 microm), and exhibited increased [3H]-thymidine uptake (160,000+/-22,300 versus 63,100+/-12,100 counts per minute) when compared with KO SMCs. Gelatin zymograms showed that WT SMCs expressed latent matrix metalloproteinase 2, whereas KO SMCs did not. Addition of exogenous type VIII collagen returned levels of KO SMC adhesion (OD595=0.316+/-0.038), migration (79.5+/-5.8 microm), and latent matrix metalloproteinase 2 expression to levels comparable to WT SMCs. CONCLUSIONS: This study suggests that SMCs can modify the matrix microenvironment by producing type VIII collagen, using it to overlay type I collagen, and generating a substrate favorable for migration.