Knockout of matrix metalloproteinase‐9 rescues the development of cognitive impairments in hypertensive Dahl salt sensitive rats
Authors: Fan Fan , Wang Shaoxun , Mims Paige N , Maeda Kenji J , Li Longyang , Geurts Aron M , Roman Richard J 
Published: November 2023

MMP‐9 is a member of the matrix metalloproteinases family of enzymes that degrade collagen and fibronectin. It regulates neutrophil migration cross the basement membrane, and plays an important role in angiogenesis and extracellular matrix remodeling associated with various physiological or pathological processes. Recent studies indicated that the expression of MMP‐9 is elevated after cerebral ischemia and is involved in accelerating matrix degradation and disrupting the blood‐brain barrier. MMP9 has a diverse effect in Alzheimer's disease (AD), it is neurotoxic by indirectly facilitating tau aggregation, but evidence also suggested that it may contribute to clearance of amyloid‐beta plaques by degrading the fibrils. However, very little is known about whether MMP9 modulates the progression of stroke, cognitive impairments or AD, and whether the mechanisms are involved in the regulation of cerebral vascular function. The present study examined the role of MMP9 in the development of hypertension‐induced cognitive impairments using a MMP9 knockout (KO) rat in the Dahl salt sensitive (SS) genetic background that we created. Baseline mean arterial pressure measured by telemetry was similar in 12‐week old MMP9 KO (n = 8) and SS rats (n = 49) fed a low salt diet, and averaged 125± 2 vs. 119 ± 2 mmHg, respectively. Proteinuria was significantly lower in MMP9 KO rats than in SS rats fed a low salt diet (60 ± 5 mg/day, n = 22 versus 101 ± 8 mg/day, n = 19). Protein excretion remained significantly lower in MMP9 KO than SS rats fed a 8% NaCl diet for 3 weeks (248 ± 26 mg/day, n=11 vs. 437 ± 39 mmHg, n = 17). The diameter of the isolated perfused middle cerebral artery (MCA) decreased to 78 ± 7 % in MMP9 KO rats when pressure was increased from 40 to 140 mmHg. In contrast, the myogenic response of the MCA isolated from SS rats did not constrict. CBF increased by 27 ± 2% (n = 8) in MMP9 KO than in SS rats (64 ± 4%, n = 10), respectively, when MAP was increased from 100 to 180 mmHg. CBF fell by 30 ± 3% (n = 9) in hypertensive MMP9 KO rats vs. 51 ± 2% (n = 10) in hypertensive SS rats when MAP was decreased from 100 to 40 mmHg. The MMP9 KO rats were 2 times as fast in escaping from an eight‐arm water maze in comparison with SS rats after induction of hypertension with a high salt diet for 3 weeks, suggesting the learning and memory deficits in hypertensive SS rats were rescued. These findings indicate that knockout of MMP9 protects against the development of proteinuria, enhances the myogenic response and autoregulation of cerebral blood flow and rescues the progression of cognitive dysfunction in hypertensive SS rats. Our studies suggest that the role of MMP9 in cognitive impairments may be involved in the regulation of cerebral vascular function. Further research is needed to understand the mechanism of MMP9 to design specific drugs and devise therapeutic strategies for dementia.Support or Funding InformationThis study was supported by grants HL36279 (RJR) and DK104184 (RJR), AG050049 (FF), P20GM104357 (RJR and FF) from the National Institutes of Health; 16GRNT31200036 (FF) from the American Heart Association. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.