Structural Weakness: Collagen Alterations in Cerebral Aneurysm Development

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

Abstract:

• Rephrase the phrase "in vivo tools" on line 37 to make it more understandable. Which tools?
• Keywords should be given alphabetically.

Introducion

• A brief literature review on the genetic and inflammatory mechanisms of the disease should be included at the end of the first paragraph. ECM disruption is of particular importance in this regard. Although detailed information is provided in the results section, it should also be included in the introduction section for the sake of completeness.
• Please provide paragraph 2 after paragraph 4, or synthesize these two paragraphs into a single paragraph to maintain the flow of meaning. Otherwise, the flow of information about collagen will be fragmented.

Material and Method

• Well written.

Results

• The information given under the heading “3.2. Pathophysiology of Aneurysm Formation,” particularly regarding the NO mechanism and NO regulation, is very superficial and the mechanism is omitted by citing a lack of literature. Please discuss the effects of NO dysregulation on anormy more clearly.
• The section titled “3.4. Molecular and Genetic Mechanisms” is very detailed and well-written, but there is a problem with the flow. Please revise the title to make it more general rather than specific.
• Under the heading “3.6. Sex and Age Differences in Collagen Remodeling,” age-related ECM degradation is described, but the relationship of this process with other molecular aging mechanisms such as oxidative stress, mitochondrial dysfunction, and epigenetic changes is not addressed comprehensively enough.

Conclusion

• Well written.

Author Response

Thank you for taking the time to review this manuscript. Your feedback has greatly improved the quality of our work. Please see the responses below that contain the actions taken to amend each comment. 

Comment 1: Rephrase the phrase "in vivo tools" on line 37 to make it more understandable. Which tools?

Response 1: Thank you for pointing this out. We have included examples of clinical methods of determining collagen breakdown added. (Line 35)

Comment 2: Keywords should be given alphabetically.

Response 2: Thank you for the keen eye. We have rearranged the Keywords to be alphabetical (lines. 43-44). 

Comment 3: A brief literature review on the genetic and inflammatory mechanisms of the disease should be included at the end of the first paragraph. 

Response 3: We thank the reviewer for this valuable suggestion. We agree that providing a concise overview of the genetic and inflammatory mechanisms underlying aneurysm pathobiology would strengthen the Introduction and improve contextual continuity. Accordingly, we have a few sentences at the end of the fifth paragraph that introduce these topics(lines 88-90). Detailed mechanistic discussions remain in the later sections to avoid redundancy while ensuring completeness.

Comment 4: Please provide paragraph 2 after paragraph 4, 

Response 4: We agree that keeping the discussion on collagen together would benefit the paper. The paragraphs have been arranged in an order to improve flow. 

Comment 5: The information given under the heading “3.2. Pathophysiology of Aneurysm Formation,” particularly regarding the NO mechanism and NO regulation, is very superficial and the mechanism is omitted by citing a lack of literature. Please discuss the effects of NO dysregulation on anormy more clearly.

Response 5: This section was expanded to describe the transition from a physiological amount of NO generated by eNOS to the pathological level of NO from iNOS (lines 189-194).

Comment 6: The section titled “3.4. Molecular and Genetic Mechanisms” is very detailed and well-written, but there is a problem with the flow. Please revise the title to make it more general rather than specific.

Response 6: We agreed in making the title more general. We have changed the title to "3.4. Biological Determinants of Aneurysm Susceptibility." 

Comment 7: Under the heading “3.6. Sex and Age Differences in Collagen Remodeling,” age-related ECM degradation is described, but the relationship of this process with other molecular aging mechanisms such as oxidative stress, mitochondrial dysfunction, and epigenetic changes is not addressed comprehensively enough.

Response 7: Thank you for the insight. We found this idea to make the section much more comprehensive. In response, we have included discussion on these topics in section "3.6 Sex and Age Differences in Collagen Remodeling" (lines 451-465). 

Reviewer 2 Report

Comments and Suggestions for Authors

Thank you for the opportunity to review this paper.

The aim of this narrative review is to provide a synthesis of the existing data about the structure and the pathophysiology of the collagen dysregulation in the initiation and progression of the intracranial aneurysms. The factors and mechanisms involved in the aneurysm formation and progression were described in detail. 

Minor comments:

-The paper include a detailed description of the role of the hemodynamic and hormonal factors in the pathophysiology of the intracranial aneyrism formation. Please add comments about the role of comorbidities in this pathophysiology (in the collagen remodelling process, the repair mechanisms , turnover rate, MMPs, etc). Is there an comorbidity-relatedimpact on the aneurysm rupture risk and the post-interventional outcome, via collagen dysregulation?

- The paragraph 3.3 provide a comparative analysis  aortic vs. cerebral aneurysms. Please add a comment about their coexistence (eventually comorbidities-related)

Author Response

We greatly appreciate your time and effort in reviewing this manuscript. We found your feedback to be very helpful. Please find the detailed responses below and the corresponding revisions/corrections highlighted/in track changes in the re-submitted files. 

Comment 1: Please add comments about the role of comorbidities in this pathophysiology (in the collagen remodelling process, the repair mechanisms , turnover rate, MMPs, etc). 

Response 1: We agree that this addition to the paper would enhance the quality. In response, we have included a commentary on how hypertension and smoking can accelerate this pathogenesis that can be found in the final paragraph of section 3.2. Pathophysiology of Aneurysm Formation (lines 238-253). 

Comment 2: The paragraph 3.3 provide a comparative analysis  aortic vs. cerebral aneurysms. Please add a comment about their coexistence (eventually comorbidities-related)

Response 2: Thank you for the insight. We believe this is a great addition to the paper. In response, we have added a paragraph at the end of section 3.3. Pathophysiology of Aneurysm Formation that frames aortic and cerebral aneurysms together, as results of an overall arterial disease (lines 299-305). 

Reviewer 3 Report

Comments and Suggestions for Authors

Hranec et al. present a narrative review concerning collagen alterations in the wall of cerebral aneurysms. The purpose of the review is to present what is known about alterations in collagen homeostasis and aneurysm formation and to identify critical gaps in knowledge to provide a direction for future investigation and potential new treatments.

The Introduction provides a complete but succinct picture of the disease. The Methods employed standard search strategies with relevant literature databases. After identifying 348 possible articles, 67 articles were included after exclusion criteria were applied.

In the various sections of Results, considerations of arterial wall structure, biochemistry, and pathophysiology are presented, containing information that is focused. A section comparing aortic to cerebral aneurysms is included, and while such a comparison is not central to the theme of this review, this reviewer can understand why the authors would think this is important to the readership. The molecular/genetic section is comprehensive, and the imaging section equally of interest. The remaining sections concerning sex-based differences, prevention, and treatment are also of great potential use to the readership. Lastly, the section concerning the gaps of knowledge and future directions is brief but fair.

Overall, I do not have any major criticisms of this work. However, it only contains one table and no figures. I would like to see at least two detailed figures, with one displaying the usual cerebral arterial wall with its layers and relevant biochemical interaction, including collagen homeostasis. The other figure should have critical pathology and potential treatment/prevention displayed in relationship to a cerebral arterial wall. Given the complexity of this subject, the review would be greatly enhanced with better visual representations of their timely work.

Author Response

Thank you for taking the time and effort to review this paper. Your feedback has been largely impactful in improving our work. 

Comment 1:  I would like to see at least two detailed figures, with one displaying the usual cerebral arterial wall with its layers and relevant biochemical interaction, including collagen homeostasis. The other figure should have critical pathology and potential treatment/prevention displayed in relationship to a cerebral arterial wall. 

Response 1: Thank you for your insight and we agree that figures could improve understanding. To account for this, we have included two figures:

Figure 1 is the general structure of an artery, with components of each wall that are relevant to aneurysm formation. 

Figure 2 will illustrates aneurysm-associated pathological remodeling in relation to the cerebral arterial wall. This figure highlights endothelial dysfunction, wall shear stress, inflammatory infiltration, oxidative stress, and malformed collagen. We chose to omit directly included potential treatment due to the lack of evidence we found for prophylactic treatment of aneurysms.  

Round 2

Reviewer 3 Report

Comments and Suggestions for Authors

No further comments.