Leading the ECM Lab is Prof. Dr. Renato<\/a>, a faculty member in the Graduate Program in Pharmacology at UNICAMP<\/a>. With a medical degree from the Federal University of Maranh\u00e3o<\/a>, a PhD from the University of Reading<\/a> (United Kingdom), and postdoctoral training at InCor-USP<\/a>, he also currently serves as an editor of the journal Circulation Research<\/a>.<\/p>\n\n\n\n His academic trajectory is marked by investigating mechanisms that increase cardiovascular risk<\/strong>. In this line of research, his studies focus especially on the role of extracellular matrix proteins<\/mark><\/strong>, as well as the modifications<\/strong> they may undergo: oxidation, reduction, and post-translational modifications<\/strong> (irreversible chemical changes in their structure). He seeks to understand how platelets, endothelial cells, and smooth muscle cells \u201csense\u201d and respond to the modified proteins<\/strong>. <\/p>\n\n\n\n From this perspective, the Extracellular Matrix Laboratory (ECM Lab)<\/mark><\/strong> is dedicated to investigating what happens outside the cell. In this space are very important matrix proteins, such as collagen, fibronectin, and fibrinogen<\/strong>. The group starts from the idea that chronic diseases<\/strong>, such as diabetes<\/strong>, promote long-lasting alterations in these proteins<\/strong>. Thus, they study how cells perceive these changes, especially in the cardiovascular context<\/strong>.<\/p>\n\n\n\n To unravel these processes, the laboratory integrates approaches ranging from molecular and biophysical analysis of proteins and their interactions to studies with cells, animal models, and patient samples. In this way, it is possible to search for new therapeutic targets for cardiovascular diseases.<\/p>\n\n\n\n Patients with diabetes have a high risk of developing cardiovascular diseases<\/strong>. Prof. Renato comments: \u201cWe conducted an epidemiological study that showed that, for the Brazilian population, when we look at risk factors for mortality from cardiovascular diseases, diabetes is by far the leading risk factor<\/strong>. Its magnitude is two to three times greater than that of other factors, such as smoking and hypertension.\u201d<\/p>\n\n\n\n There are several factors involved in this increased risk. \u201cDiabetes never comes alone. Usually, a person is diabetic, but may also be dyslipidemic, obese, sedentary, or a smoker. So there are associated risk factors,\u201d explains Prof. Renato.<\/p>\n\n\n\n In addition, diabetes itself directly affects other mechanisms involved in the risk of experiencing an ischemic event<\/strong>. Prof. Renato highlights that an important mechanism is platelet activation<\/mark><\/strong>: \u201cPlatelets in people with diabetes tend to be hyperreactive<\/strong>. As a result, they form larger thrombi<\/mark><\/strong>. This increases the likelihood of affecting an organ such as the heart or brain.\u201d<\/p>\n\n\n\n Platelets<\/strong> circulate in the blood and are essential for stopping bleeding. When a blood vessel is damaged (causing bleeding), platelets act quickly by becoming activated and aggregating<\/strong> to form a clot<\/strong>, which prevents hemorrhage. You have probably noticed that a wound stops bleeding after a short time. This happens precisely because platelets form a clot to stop the bleeding.<\/p>\n\n\n\n However, platelets in people with diabetes may react far more than normal<\/strong>. As a result, they do not respond only to injuries in blood vessels that cause bleeding. Much smaller stimuli can trigger a reaction<\/strong>, such as microlesions in the vessels and changes in blood flow.<\/p>\n\n\n\n This can lead to the formation of clots within blood vessels<\/strong>, known as thrombi<\/mark><\/strong>. In people with diabetes, these thrombi can become large enough to obstruct small vessels in the heart or brain, leading to myocardial infarction and stroke, respectively<\/strong>. In other words, once the vessel is \u201cblocked,\u201d blood can no longer circulate and deliver oxygen to that area, resulting in cell death.<\/p>\n\n\n\n However, a mystery has puzzled researchers for decades. It is known that even after glycemic control is achieved, cardiovascular risk often remains elevated<\/strong>. Prof. Renato comments: \u201cDiabetic patients are usually prescribed metformin<\/strong>. However, we still do not have robust studies showing that metformin will reduce the likelihood of a person having a heart attack.\u201d<\/p>\n\n\n\n In recent years, so-called \u201cweight-loss pens<\/strong>,\u201d such as Ozempic and Mounjaro, have revolutionized diabetes treatment. Prof. Renato notes: \u201cIf you look at these medications, they reduce mortality by approximately 15%. […] So even these more modern drugs may not provide very efficient protection<\/strong>.\u201d<\/p>\n\n\n\n The reason why cardiovascular risk remains high even after glycemic control is still unclear<\/strong>. For this reason, the ECM Lab decided to investigate this relationship<\/strong> (Funding: S\u00e3o Paulo Research Foundation \u2013 FAPESP, grant no. 22\/05750-7<\/a>). One of the hypotheses points to the role of glycated collagen<\/mark><\/strong>. This is a modified form of collagen that accumulates damage over years of hyperglycemia<\/strong>. This process is known as glycation<\/mark><\/strong>.<\/p>\n\n\n\n In glycation<\/strong>, sugar molecules bind to other molecules<\/strong>, such as proteins. In the case of collagen, when glycated, it forms larger and stiffer fibers than normal. This reaction cannot be reversed<\/strong>, as it involves covalent bonds, that is, the sharing of electrons between atoms within a molecule. It is as if glucose were bound to collagen with concrete, making them inseparable.<\/p>\n\n\n\n Doctoral student and laboratory technician M.Sc. Tatiana Toledo<\/a> explains the rationale behind investigating collagen: \u201cBetween the onset of hyperglycemia and the diagnosis of diabetes, there is a gap of around five years. Collagen is a long half-life protein<\/strong>.\u201d This means that the same collagen molecule can remain in the body for more than 10 years<\/strong> without being replaced.<\/p>\n\n\n\n M.Sc. Tatiana adds: \u201cBecause it is a protein exposed to everything that happens inside the body, it can undergo modifications such as glycation<\/strong>. We can draw a parallel with glycated hemoglobin, which is used as a parameter for diabetes diagnosis. However, hemoglobin is replaced within 120 days. Collagen is not. So, over time, there is an accumulation of modifications in collagen.\u201d<\/p>\n\n\n\n Due to its long half-life, collagen functions as a kind of \u201cmolecular memory<\/mark><\/strong>\u201d of the disease, potentially retaining alterations caused by hyperglycemia even after it has been treated<\/strong>. This process has already been shown to play a role in impaired wound healing in diabetes. Currently, the ECM Lab is investigating whether collagen glycation may contribute to increased cardiovascular risk, for example, by making blood vessels stiffer or by altering platelet reactivity<\/strong>.<\/p>\n\n\n\n Doctoral students M.Sc. R\u00f4mulo Fr\u00f3es<\/a> and Samuel Maia<\/a> were drawn to the group precisely because of the study\u2019s unique approach. M.Sc. R\u00f4mulo explains: \u201cThe innovation factor is what attracted me. There are very few studies linking glycated collagen to cardiovascular diseases.\u201d<\/p>\n\n\n\n Samuel adds: \u201cWhat sparked my curiosity to work on this project was learning that there is this subgroup of diabetes patients who remain susceptible to very serious cardiovascular outcomes. The project focuses on a group that is often overlooked and may even help us find ways to address this issue.\u201d<\/p>\n\n\n\n The project is quite ambitious and involves the participation of several students. Prof. Renato explains: \u201cThe idea is to work from the isolated protein, through the cell, all the way to the patient. So far, we have managed to study the isolated protein, cells, and animal models. Soon, we will begin working with patients.\u201d<\/p>\n\n\n\n In animal models, the researchers use two drugs to induce collagen glycation: streptozotocin<\/mark> and methylglyoxal<\/mark><\/strong>. Streptozotocin<\/strong> leads to the destruction of pancreatic \u03b2 (beta) cells<\/strong>, which are responsible for insulin production<\/strong>. Insulin<\/strong> is an essential hormone for glycemic control, as it allows glucose in the bloodstream to enter cells<\/strong>, thereby lowering blood glucose levels.<\/p>\n\n\n\n Thus, after the administration of streptozotocin<\/strong>, insulin production decreases<\/strong> and, consequently, hyperglycemia<\/strong> develops. This condition closely resembles type 1 diabetes<\/strong>, in which the individual has little or no insulin production. With hyperglycemia, collagen glycation<\/strong> occurs.<\/p>\n\n\n\n The other drug used is methylglyoxal<\/strong>, a byproduct of glucose<\/strong> produced by our body. In the process known as metabolism, the body chemically modifies glucose to facilitate its excretion, generating methylglyoxal and other molecules. Methylglyoxal does not cause hyperglycemia<\/strong>, but it is highly reactive<\/strong>, leading to the glycation of several molecules<\/strong> in the body, such as collagen.<\/p>\n\n\n\n Master\u2019s student Nat\u00e1lia Oliveira<\/a>, who works exclusively with animals treated with methylglyoxal<\/strong>, highlights the importance of this approach: \u201cI measured the blood glucose levels of my animals. They were not diabetic<\/strong>. With methylglyoxal, I can observe something much more specific: only collagen glycation<\/strong>. Just this final product that would result from hyperglycemia, without actually inducing hyperglycemia itself. The diabetes condition.\u201d<\/p>\n\n\n\n Several students work on the same project, but each has a specific role. Each one is responsible for uncovering a different part of the story. Prof. Renato explains: \u201cSince I am at the beginning of setting up my lab, I designed projects that are highly interconnected. Each student has their own project, but they also have a counterpart working on something similar. So I always encourage students to collaborate with one another.\u201d<\/p>\n\n\n\n At the ECM Lab, students at different academic levels work with glycated collagen: undergraduate researcher Beatriz da Silva<\/a> (FAPESP grant no. 25\/23132-7<\/a>); master\u2019s student Nat\u00e1lia Silva Oliveira (FAPESP grant no. 24\/00842-6<\/a>); and doctoral students M.Sc. R\u00f4mulo Fr\u00f3es (FAPESP grant no. 24\/07470-7<\/a>) and Samuel Maia (FAPESP grant no. 24\/02620-0<\/a>).<\/p>\n\n\n\n Beatriz and M.Sc. R\u00f4mulo focus on platelet response<\/mark><\/strong>. M.Sc. R\u00f4mulo explains: \u201cMy hypothesis is that, in a scenario of chronic hyperglycemia (as in diabetes), collagen undergoes glycation, which alters platelet response, leading to the development of cardiovascular diseases, especially thrombotic ones<\/strong>.\u201d<\/p>\n\n\n\n And this is exactly what has been observed, as M.Sc. R\u00f4mulo explains: \u201cGlycated collagen increases both platelet aggregation and platelet adhesion<\/strong>.\u201d This finding is particularly relevant. If glycated collagen makes platelets more prone to aggregation and adhesion, it facilitates thrombus formation and, consequently, the occurrence of myocardial infarction or stroke<\/strong>.<\/p>\n\n\n\n Doctoral student Samuel<\/strong> also investigates platelet function<\/strong>, but his focus is endothelial dysfunction in diabetes<\/mark><\/strong>, which is essential for proper vascular function. He therefore conducts animal experiments to assess vascular reactivity<\/strong>.<\/p>\n\n\n\n Understanding endothelial dysfunction<\/strong> is key to unraveling cardiovascular risk in diabetes. The endothelium is a layer of cells that lines the inner surface of blood vessels<\/strong>. These cells play a central role in regulating vascular tone, blood flow, and the balance between procoagulant and anticoagulant factors. When the endothelium does not function properly, there is impaired vessel dilation, increased inflammation, and a higher likelihood of thrombus formation<\/strong>.<\/p>\n\n\n\n Master\u2019s student Nat\u00e1lia<\/strong> also investigates vascular reactivity<\/mark><\/strong>. She explains: \u201cMy focus is the thoracic aorta<\/strong>. This allows me to investigate how much glycated collagen is associated with vascular events.\u201d<\/p>\n\n\n\n While Samuel induces diabetes using streptozotocin, Nat\u00e1lia focuses solely on collagen glycation through the use of methylglyoxal<\/strong>. Nat\u00e1lia notes that, despite the different drugs used, their results are directly comparable: \u201cEven so, we obtained identical results regarding vessel stiffness<\/strong>.\u201d Samuel adds: \u201cWe observed that the damage was very similar between the two models, such as vascular remodeling damage<\/strong>.\u201d<\/p>\n\n\n\n Prof. Renato further comments on the findings: \u201cWe observed that the aorta relaxes just as much as a control aorta, both in methylglyoxal-treated animals and in diabetic animals<\/strong>. In other words, endothelial function is preserved. However, the contraction of this vessel is increased<\/strong>. So perhaps the long-term impact of this glycation is more prominent in the vascular smooth muscle than in the endothelium<\/strong>.\u201d<\/p>\n\n\n\n This result is important because it helps identify exactly where the problem lies in the blood vessels. Vessels need both to relax and to contract in order to regulate blood flow<\/strong>. The researchers observed that relaxation remains normal. Since the endothelium is primarily responsible for relaxation<\/strong>, they concluded that it is not affected by collagen glycation.<\/p>\n\n\n\n On the other hand, vessel contraction is increased<\/strong>, which may cause vessels to become more \u201cconstricted\u201d than they should be<\/strong>. This suggests that glycated collagen primarily affects the vascular smooth muscle, which is responsible for regulating contraction<\/strong>.<\/p>\n\n\n\n An interesting aspect of Nat\u00e1lia\u2019s project is that she performs a \u201cwashout<\/strong>\u201d period in her animals, as explained by Prof. Renato: \u201cWe administered methylglyoxal for 12 weeks and then withdrew it for 4 weeks. The idea was to observe the long-term effects of methylglyoxal on vascular reactivity in these animals<\/strong>.\u201d This approach is based on the assumption that collagen becomes glycated during exposure to methylglyoxal and remains so even after the drug is withdrawn.<\/p>\n\n\n\n In addition, Nat\u00e1lia treats some animals with metformin<\/mark><\/strong> after this period. This is one of the most commonly prescribed drugs for the treatment of diabetes. Metformin reduces glucose production in the liver and improves insulin sensitivity, thereby helping to control blood glucose levels<\/strong>.<\/p>\n\n\n\n By using metformin, Nat\u00e1lia is able to assess whether a widely used diabetes medication can attenuate the effects of collagen glycation. However, the researcher notes that this treatment appears to have no effect<\/strong>.<\/p>\n\n\n\n This finding closely parallels clinical reality<\/strong>. We observe that cardiovascular risk persists even after patients have achieved glycemic control and are receiving pharmacological treatment<\/strong>. This highlights the importance of developing new therapeutic strategies.<\/p>\n\n\n\n Having multiple students working on parallel yet interconnected projects makes the ECM Lab<\/mark><\/strong> a highly collaborative environment<\/strong>. Prof. Renato explains that he consistently encourages students to work together: \u201cWe have meetings every Friday. During these, students share what they have done throughout the week.\u201d<\/p>\n\n\n\n Prof. Renato also has a very insightful perspective on work within the lab: \u201cScience is a creative process<\/strong>. Sometimes you have an idea at night. Sometimes you don\u2019t feel like working the next day. Of course, you need some structure to support a productive creative process, but sometimes it just doesn\u2019t happen.\u201d This environment gives students room to grow while developing their projects<\/strong>.<\/p>\n\n\n\n The ECM Lab is also where Beatriz, an undergraduate Pharmacy student at UNICAMP<\/strong>, chose to carry out her first scientific initiation<\/mark><\/strong> project. She shares what it is like to be involved in such an ambitious project early in her academic journey: \u201cI won\u2019t deny that it is quite challenging<\/strong> and requires a lot of mental energy, but it is very rewarding<\/strong> to see the outcomes of the research and realize how much knowledge I have gained from my experience in the lab.\u201d<\/p>\n\n\n\n Beatriz explains that the main challenges of engaging in research include assimilating undergraduate content at a much deeper level and constantly learning new experimental techniques<\/strong>. She also shares what motivated her to join the ECM Lab team: \u201cI had always been curious about doing a research project. At the time, I was taking a pharmacology class and became interested in Prof. Renato\u2019s research line. I decided to visit the lab and loved it.\u201d<\/p>\n\n\n\n By investigating glycated collagen, researchers at the ECM Lab are helping to uncover how cardiovascular risk develops in diabetes. Long-lasting molecular changes, accumulated over time, may continue to affect vascular function even after treatment. These findings highlight the need for new therapeutic approaches that go beyond blood glucose control<\/strong>.<\/p>\n\n\n\n <\/p>\n\n\n\n This article was produced with the support of the S\u00e3o Paulo Research Foundation (FAPESP), Brazil. Grant No. 25\/17158-3. The opinions, hypotheses, conclusions, or recommendations expressed in this material are the responsibility of the author(s) and do not necessarily reflect the views of FAPESP.<\/p>\n\n\n\n <\/p>\n\n\n\n ECM Lab page<\/a><\/p>\n\n\n\n ECM Lab on Instagram<\/a><\/p>\n\n\n\n Risk factors for cardiovascular diseases in Brazil<\/a> (DOI: 10.1371\/journal.pone.0269549)<\/p>\n\n\n\n Diabetes and cardiovascular disease<\/a> (DOI: 10.29277\/cardio.36.1.4)<\/p>\n\n\n\n Treatment of cardiovascular disease in diabetes<\/a> (DOI: 10.1016\/j.repc.2018.03.013)<\/p>\n\n\n\n Collagen glycation in diabetes<\/a> (DOI: 10.2337\/diab.45.3.s67)<\/p>\n\n\n\nWhy does diabetes increase the risk of cardiovascular diseases so much?<\/strong><\/h2>\n\n\n\n
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<\/figure>\n\n\n\nThe enigma of persistent risk in diabetes<\/strong><\/h2>\n\n\n\n
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<\/figure>\n\n\n\nHow to study glycation in practice<\/strong><\/h2>\n\n\n\n
Teamwork to understand how thrombi form<\/strong><\/h2>\n\n\n\n
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Between relaxing and contracting: how glycated collagen alters vessel function<\/strong><\/h2>\n\n\n\n
When treatment does not erase the damage<\/strong><\/h2>\n\n\n\n
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Hypotheses do not always hold, but that is where science advances<\/strong><\/h2>\n\n\n\n
Learn more<\/strong>:<\/h2>\n\n\n\n
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