Microangiopathy#Pathophysiology

Microangiopathies are involved in a variety of different diseases including:

{{bulleted list |Diabetic microangiopathy, mainly as diabetic retinopathy, nephropathy and neuropathy. Nevertheless, diabetic microvascular dysfunction is not limited to the eyes, kidneys, and nerves, but can also affect other organs such as the skin, muscles, heart, and brain.

{{cite journal |last1=Sugimoto |first1=Kazuhiro |last2=Murakami |first2=Hiroshi |last3=Deguchi |first3=Takahisa |last4=Arimura |first4=Aiko |last5=Daimon |first5=Makoto |last6=Suzuki |first6=Susumu |last7=Shimbo |first7=Takuro |last8=Yagihashi |first8=Soroku |title=Cutaneous microangiopathy in patients with type 2 diabetes: Impaired vascular endothelial growth factor expression and its correlation with neuropathy, retinopathy and nephropathy |journal=Journal of Diabetes Investigation |date=2019 |volume=10 |issue=5 |pages=1318–1331 |doi=10.1111/jdi.13020 |pmid=30719863 |issn=2040-1116 |pmc=6717820}}|Coronary microvascular diseases (CMDs), which are a group of conditions affecting the microvasculature in the heart and include microvascular angina, previously known as cardiac syndrome X.{{cite journal |last1=Camici |first1=Paolo G. |last2=Crea |first2=Filippo |title=Coronary microvascular dysfunction |journal=The New England Journal of Medicine |date=22 February 2007 |volume=356 |issue=8 |pages=830–840 |doi=10.1056/NEJMra061889 |pmid=17314342 |url=https://pubmed.ncbi.nlm.nih.gov/17314342/ |issn=1533-4406}}|Cerebral small vessel diseases (CSVDs), which include arteriosclerosis-related CSVD as in hypertension, amyloid-related CSVD as in Alzheimer's disease and other genetic, inflammatory-mediated and immune-mediated CSVDs.{{cite journal |last1=Litak |first1=Jakub |last2=Mazurek |first2=Marek |last3=Kulesza |first3=Bartłomiej |last4=Szmygin |first4=Paweł |last5=Litak |first5=Joanna |last6=Kamieniak |first6=Piotr |last7=Grochowski |first7=Cezary |title=Cerebral Small Vessel Disease |journal=International Journal of Molecular Sciences |date=20 December 2020 |volume=21 |issue=24 |pages=9729 |doi=10.3390/ijms21249729 |pmid=33419271 |issn=1422-0067 |pmc=7766314 |doi-access=free }}{{CC-notice|cc=by4}}|Thrombotic microangiopathies, pseudo-thrombotic microangiopathy{{cite journal |last1=Pereira Fontes |first1=Carla |last2=Fonseca |first2=Samuel |title=Pseudothrombotic Microangiopathy as a Rare Presentation of Cobalamin Deficiency |journal=Cureus |date=2021 |volume=13 |issue=8 |pages=e17184 |doi=10.7759/cureus.17184 |doi-access=free |pmid=34540418 |issn=2168-8184 |pmc=8439408}} and microangiopathies in a wide range of diseases including COVID-19 infection,{{cite journal |last1=Gualtierotti |first1=Roberta |last2=Fox |first2=Sharon E. |last3=Da Silva Lameira |first3=Fernanda |last4=Giachi |first4=Andrea |last5=Valenti |first5=Luca |last6=Borghi |first6=Maria Orietta |last7=Meroni |first7=Pier Luigi |last8=Cugno |first8=Massimo |last9=Peyvandi |first9=Flora |title=Nailfold Videocapillaroscopic Alterations as Markers of Microangiopathy in COVID-19 Patients |journal=Journal of Clinical Medicine |date=28 May 2023 |volume=12 |issue=11 |pages=3727 |doi=10.3390/jcm12113727 |pmid=37297922 |issn=2077-0383 |pmc=10253962 |doi-access=free }}{{CC-notice|cc=by4}} chronic kidney disease,{{cite journal |last1=Prommer |first1=Hans-Ulrich |last2=Maurer |first2=Johannes |last3=von Websky |first3=Karoline |last4=Freise |first4=Christian |last5=Sommer |first5=Kerstin |last6=Nasser |first6=Hamoud |last7=Samapati |first7=Rudi |last8=Reglin |first8=Bettina |last9=Guimarães |first9=Pedro |last10=Pries |first10=Axel Radlach |last11=Querfeld |first11=Uwe |title=Chronic kidney disease induces a systemic microangiopathy, tissue hypoxia and dysfunctional angiogenesis |journal=Scientific Reports |date=28 March 2018 |volume=8 |issue=1 |pages=5317 |doi=10.1038/s41598-018-23663-1 |pmid=29593228 |issn=2045-2322 |pmc=5871820|bibcode=2018NatSR...8.5317P }} chronic venous insufficiency,{{cite journal |last1=Franzeck |first1=U. K. |last2=Haselbach |first2=P. |last3=Speiser |first3=D. |last4=Bollinger |first4=A. |title=Microangiopathy of cutaneous blood and lymphatic capillaries in chronic venous insufficiency (CVI). |journal=The Yale Journal of Biology and Medicine |date=1993 |volume=66 |issue=1 |pages=37–46 |pmid=8256463 |issn=0044-0086 |pmc=2588834}} systemic scleroderma and other connective tissue diseases (CTDs) associated with peripheral vascular syndrome,{{cite journal |last1=Lambova |first1=Sevdalina Nikolova |title=Microangiopathy in Rheumatic Diseases |journal=Life |date=10 February 2023 |volume=13 |issue=2 |pages=491 |doi=10.3390/life13020491 |pmid=36836847 |issn=2075-1729 |pmc=9965541 |doi-access=free }} sarcoidosis,{{cite journal |last1=Martinelli |first1=Anthony W. |last2=Dunn |first2=William |last3=McClure |first3=Mark E. |last4=Walker |first4=Ieuan |last5=Stewart |first5=Andrew |last6=Karia |first6=Sumit |last7=Preston |first7=Stephen D. |last8=Thiru |first8=Sathia |last9=Torpey |first9=Nicholas |last10=Ojha |first10=Sanjay |last11=Symington |first11=Emily |last12=Nathan |first12=James A. |title=A Case of Thrombotic Microangiopathy and Acute Sarcoidosis |journal=Chest |date=November 2022 |volume=162 |issue=5 |pages=e245–e248 |doi=10.1016/j.chest.2022.06.023 |pmid=36344132 |issn=0012-3692 |pmc=9752182}} amyloidosis{{cite journal |last1=Koike |first1=Haruki |last2=Katsuno |first2=Masahisa |title=Ultrastructure in Transthyretin Amyloidosis: From Pathophysiology to Therapeutic Insights |journal=Biomedicines |date=5 February 2019 |volume=7 |issue=1 |pages=11 |doi=10.3390/biomedicines7010011 |pmid=30764529 |issn=2227-9059 |pmc=6466231 |doi-access=free }} and even with long-haul flights.{{cite journal |last1=Cesarone |first1=M. R. |last2=Belcaro |first2=G. |last3=Geroulakos |first3=G. |last4=Griffin |first4=M. |last5=Ricci |first5=A. |last6=Brandolini |first6=R. |last7=Pellegrini |first7=L. |last8=Dugall |first8=M. |last9=Ippolito |first9=E. |last10=Candiani |first10=C. |last11=Simeone |first11=E. |last12=Errichi |first12=B. M. |last13=Di Renzo |first13=A. |title=Flight microangiopathy on long-haul flights: prevention of edema and microcirculation alterations with Venoruton |journal=Clinical and Applied Thrombosis/Hemostasis|date=April 2003 |volume=9 |issue=2 |pages=109–114 |doi=10.1177/107602960300900203 |pmid=12812378 |s2cid=1605773 |issn=1076-0296|doi-access=free }}}}

The main target of small vessel diseases is the endothelium, which plays a key role in vascular homeostasis. The pathogenesis of SVDs in various organs is characterized by endothelial dysfunction, capillary rarefaction, microthrombi and microvascular remodeling.{{cite journal |last1=Feuer |first1=Daniel S. |last2=Handberg |first2=Eileen M. |last3=Mehrad |first3=Borna |last4=Wei |first4=Janet |last5=Merz |first5=C. Noel Bairey |last6=Pepine |first6=Carl J. |last7=Keeley |first7=Ellen C. |title=Microvascular dysfunction as a systemic disease: A review of the evidence |journal=The American Journal of Medicine |date=2022 |volume=135 |issue=9 |pages=1059–1068 |doi=10.1016/j.amjmed.2022.04.006 |pmid=35472396 |url=https://www.amjmed.com/article/S0002-9343(22)00341-2/fulltext |issn=0002-9343 |pmc=9427712}}

Diabetic microangiopathy, which is the most common cause of microangiopathy, is more prevalent in the kidney, retina and vascular endothelium since glucose transport in these sites isn’t regulated by insulin and these tissues cannot stop glucose from entering cells when blood sugar levels are high.{{cite journal |last1=Khalil |first1=H. |title=Diabetes microvascular complications-A clinical update |journal=Diabetes & Metabolic Syndrome |date=November 2017 |volume=11 |issue=Suppl 1 |pages=S133–S139 |doi=10.1016/j.dsx.2016.12.022 |pmid=27993541 |url=https://www.sciencedirect.com/science/article/abs/pii/S1871402116302648 |issn=1878-0334}} Among all biochemical mechanisms involved in diabetic vascular damage such as the polyol pathway and the renin–angiotensin system (RAS), the advanced glycation end products (AGEs) pathway appears to be the most important in the pathogenesis and progression of microvascular complications.{{cite journal |last1=Mengstie |first1=Misganaw Asmamaw |last2=Chekol Abebe |first2=Endeshaw |last3=Behaile Teklemariam |first3=Awgichew |last4=Tilahun Mulu |first4=Anemut |last5=Agidew |first5=Melaku Mekonnen |last6=Teshome Azezew |first6=Muluken |last7=Zewde |first7=Edgeit Abebe |last8=Agegnehu Teshome |first8=Assefa |title=Endogenous advanced glycation end products in the pathogenesis of chronic diabetic complications |journal=Frontiers in Molecular Biosciences |date=15 September 2022 |volume=9 |pages=1002710 |doi=10.3389/fmolb.2022.1002710 |pmid=36188225 |issn=2296-889X |pmc=9521189 |doi-access=free }}

Chronic high blood sugar levels lead to the attachment of sugar molecules to various proteins, including collagen, laminin, and peripheral nerve proteins. This process, called glycosylation, creates advanced glycation end products (AGEs). AGEs formation cross-links these proteins, making them resistant to degradation. This leads to accumulation of AGEs, thickening of the basement membrane, narrowing the blood vessels, reducing blood flow to the tissues and causing ischemic injury.{{cite book |last1=Cecil |first1=Russell La Fayette |last2=Goldman |first2=Lee |last3=Schafer |first3=Andrew I. |title=Goldman's Cecil medicine |date=2012 |publisher=Elsevier/Saunders |location=Philadelphia |isbn=978-1-4377-1604-7 |edition=24th}}{{cite journal |last1=Somboonwong |first1=Juraiporn |last2=Yusuksawad |first2=Mariem |last3=Keelawat |first3=Somboon |last4=Thongruay |first4=Sirima |last5=Poumsuk |first5=Ubon |title=Minimization of the Risk of Diabetic Microangiopathy in Rats by Nigella sativa |journal=Pharmacognosy Magazine |date=2016 |volume=12 |issue=Suppl 2 |pages=S175–S180 |doi=10.4103/0973-1296.182169 |pmid=27279704 |issn=0973-1296 |pmc=4883076 |doi-access=free }}

In addition, oxidative stress, caused by AGEs and the other pathways, causes apoptosis of pericytes and podocytes in the retina and the kidneys respectively leading to capillary wall fragility and increased vascular leakage. This results in local swelling (e.g. macular edema) and impaired tissue function.{{cite journal |last1=Madonna |first1=Rosalinda |last2=Balistreri |first2=Carmela Rita |last3=Geng |first3=Yong-Jian |last4=De Caterina |first4=Raffaele |title=Diabetic microangiopathy: Pathogenetic insights and novel therapeutic approaches |journal=Vascular Pharmacology |date=March 2017 |volume=90 |pages=1–7 |doi=10.1016/j.vph.2017.01.004 |pmid=28137665 |url=https://core.ac.uk/reader/98114493 |issn=1879-3649}}

Some researchers have suggested that SVD may be a multisystem disorder, meaning that it can affect multiple organs in the body, including the heart and brain. This is supported by multiple studies stating that cardiac pathologies are more prevalent in patients with pathological evidence of cerebrovascular SVD and vice versa.{{cite journal |last1=Berry |first1=Colin |last2=Sidik |first2=Novalia |last3=Pereira |first3=Anthony C. |last4=Ford |first4=Thomas J. |last5=Touyz |first5=Rhian M. |last6=Kaski |first6=Juan-Carlos |last7=Hainsworth |first7=Atticus H. |title=Small-Vessel Disease in the Heart and Brain: Current Knowledge, Unmet Therapeutic Need, and Future Directions |journal=Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease |date=2 February 2019 |volume=8 |issue=3 |pages=e011104 |doi=10.1161/JAHA.118.011104 |pmid=30712442 |issn=2047-9980 |pmc=6405580}}{{CC-notice|cc=by4}}

Coronary microvascular diseases (CMDs) can be caused by:

{{bulleted list |Structural changes, such as vascular remodeling and increased thickness and hypertrophy of arterial walls present in hypertrophic cardiomyopathy. |Functional changes, such as endothelial dysfunction caused by oxidative damage as in smoking. |Extravascular changes, such as left ventricular hypertrophy and high left ventricular pressure as a result of aortic stenosis (AS).}}

On the other hand, Cerebral SVD encompasses a range of vascular pathologies including arteriosclerosis-related CSVD, where lipohyalinosis causes stenosis of the lumen of the arterioles and amyloid-related CSVD, characterized by the build-up of β-amyloid deposits in small- and medium-caliber cerebral vessels.

The vascular anatomy of the heart and brain is similar in that conduit arteries are distributed on the surface of these organs with tissue perfusion achieved through deep penetrating arteries. Both coronary and cerebral microvascular diseases do share some common risk factors such as hypertension. Why some patients with microvascular angina subsequently develop vascular cognitive impairment and others do not is an unanswered question. Potential underpinning mechanisms include premature vascular aging and clustering of vascular risk factors leading to an accelerated cardiovascular risk.

{{See also|Diabetic retinopathy#Diagnosis and classification|Diabetic nephropathy#Diagnosis|Diabetic neuropathy#Diagnosis}}

The diagnosis of microangiopathies can be based on direct visualization of the microcirculation, imaging modalities (e.g. MRI), conventional testings (e.g. ophthalmoscopy for diabetic retinopathy) or other diagnostic measures (e.g. blood smear for schistocytes in thrombotic microangiopathies).

For assessment of the morphological and functional aspects of microcirculation, nailfold videocapillaroscopy (NVC) can be used, in which videocapillaroscopy is performed at the nailfold, where capillaries are arranged with the longitudinal axis parallel to the skin surface, so that they can be examined along their entire length.

NVC has been largely used not only for investigating peripheral microangiopathy, but also as a sort of "window" to systemic microvascular dysfunction. Although its main application is within the connective tissue diseases such as systemic scleroderma and dermatomyositis, it has been employed in non-rheumatic diseases with microvascular involvement such as diabetes mellitus, essential hypertension and COVID-19 infection.

File:MVD003.png

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Optical coherence tomography angiography (OCTA) is another imaging modality that offers high-resolution visualization of the retinal capillary network and can be used to evaluate microcirculation in conditions such as diabetic retinopathy.{{cite journal |last1=Le |first1=Patrick H. |last2=Patel |first2=Bhupendra C. |title=Optical Coherence Tomography Angiography |journal=StatPearls |date=2023 |pmid=33085382 |url=https://www.ncbi.nlm.nih.gov/books/NBK563235/ |access-date=29 September 2023 |publisher=StatPearls Publishing}}

Many studies have demonstrated that evaluation of the retinal microvascular changes using OCTA or other methods such as fluorescein angiography may reflect the systemic microvascular functions as in patients with coronary microvascular disease, cerebral small vessel diseases or systemic sclerosis (The potential of retinal microvascularopathy as a biomarker for assessing microvascular status of other circulations).{{cite journal |last1=Sideri |first1=Anna-Maria |last2=Kanakis |first2=Menelaos |last3=Katsimpris |first3=Andreas |last4=Karamaounas |first4=Aristotelis |last5=Brouzas |first5=Dimitrios |last6=Petrou |first6=Petros |last7=Papakonstaninou |first7=Evangelia |last8=Droutsas |first8=Konstantinos |last9=Kandarakis |first9=Stylianos |last10=Giannopoulos |first10=Georgios |last11=Georgalas |first11=Ilias |title=Correlation Between Coronary and Retinal Microangiopathy in Patients With STEMI |journal=Translational Vision Science & Technology |date=5 May 2023 |volume=12 |issue=5 |pages=8 |doi=10.1167/tvst.12.5.8 |pmid=37145590 |issn=2164-2591 |pmc=10168007}}{{cite journal |last1=Tang |first1=Qian |last2=Zhang |first2=Yanli |last3=Yang |first3=Zhengfang |last4=Li |first4=Siou |last5=Wu |first5=Meini |last6=Guo |first6=Yongming |last7=Zhao |first7=Weina |last8=Yin |first8=Changhao |title=Study on the Interaction between the Characteristics of Retinal Microangiopathy and Risk Factors for Cerebral Small Vessel Disease |journal=Contrast Media & Molecular Imaging |date=9 June 2022 |volume=2022 |pages=9505945 |doi=10.1155/2022/9505945 |pmid=35800241 |issn=1555-4309 |pmc=9203197 |doi-access=free }}

Unlike the retinal microcirculation, the coronary microvasculature cannot be directly imaged. Instead, a number of different tests can be used to measure how much blood is flowing through the coronary microvasculature. These tests can be used to assess how well the coronary microvasculature is functioning and to diagnose coronary microvascular disease. They include non-invasive measures such as cardiac MRI and invasive measures such as intracoronary Doppler wire.{{cite journal |last1=Taqueti |first1=Viviany R. |last2=Di Carli |first2=Marcelo F. |title=Coronary Microvascular Disease Pathogenic Mechanisms and Therapeutic Options: JACC State-of-the-Art Review |journal=Journal of the American College of Cardiology |date=27 November 2018 |volume=72 |issue=21 |pages=2625–2641 |doi=10.1016/j.jacc.2018.09.042 |pmid=30466521 |issn=0735-1097 |pmc=6296779}}

Similarly, CSVD is typically recognized on both brain magnetic resonance imaging (MRI) and computed tomography (CT) scans, but MRI has greater sensitivity and specificity. Neuroimaging of CSVD primarily involves visualizing radiological phenotypes of CSVD such as recent subcortical infarcts or cerebral microbleeds (CMBs).

Treatment options of microangiopathies can be directed at:

{{bulleted list |Prevention (e.g. maintaining good glycaemic control, screening for retinopathy and neuropathy and testing for albuminuria). |Controlling symptoms and preventing further deterioration (e.g. tricyclic antidepressants and gabapentin for diabetic neuropathy). |Drug therapy (e.g. antiplatelets (low-dose aspirin) and lipid-lowering therapy (statins) for management of CMDs). |Diet and lifestyle modification (e.g. low-protein diet in diabetic nephropathy, smoking cessation, weight loss, improved nutrition, and regular exercise).{{cite journal |last1=Chojdak-Łukasiewicz |first1=Justyna |last2=Dziadkowiak |first2=Edyta |last3=Zimny |first3=Anna |last4=Paradowski |first4=Bogusław |title=Cerebral small vessel disease: A review |journal=Advances in Clinical and Experimental Medicine|date=March 2021 |volume=30 |issue=3 |pages=349–356 |doi=10.17219/acem/131216 |pmid=33768739 |s2cid=232365709 |issn=1899-5276|doi-access=free }} |Intensive management of coexisting conditions and risk factors (e.g. adequate control of blood pressure, diabetes and related metabolic abnormalities and lipid management). |Other measures (e.g. photocoagulation in patients with severe proliferative diabetic retinopathy). |Young people with extensive CSVD and few or no conventional vascular risk factors may benefit from genetic testing to identify any underlying genetic disorders that may be contributing to their condition (For Fabry disease, there is an enzyme replacement therapy).}}

A better understanding of the mechanisms leading to damage of small blood vessels may be associated with novel therapeutic approaches, the safety and efficacy of some of which will need to be further investigated. Examples include calcium dobesilate and aldose reductase inhibitors in diabetic microangiopathies and endothelin receptor antagonists for pulmonary hypertension.{{Cite journal|last1=Zhang|first1=XinYuan|last2=Liu|first2=Wei|last3=Wu|first3=ShanShan|last4=Jin|first4=JingLong|last5=Li|first5=WeiHong|last6=Wang|first6=NingLi|date=2014-12-20|title=Calcium dobesilate for diabetic retinopathy: a systematic review and meta-analysis|journal=Science China Life Sciences|language=en|volume=58|issue=1|pages=101–107|doi=10.1007/s11427-014-4792-1|pmid=25528255|issn=1674-7305|doi-access=free}}{{Cite journal|last1=Haller|first1=Hermann|last2=Ji|first2=Linong|last3=Stahl|first3=Klaus|last4=Bertram|first4=Anna|last5=Menne|first5=Jan|date=2017|title=Molecular Mechanisms and Treatment Strategies in Diabetic Nephropathy: New Avenues for Calcium Dobesilate—Free Radical Scavenger and Growth Factor Inhibition|journal=BioMed Research International|language=en|volume=2017|pages=1909258|doi=10.1155/2017/1909258|issn=2314-6133|pmc=5634607|pmid=29082239|doi-access=free }}

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{{Vascular diseases}}

Category:Histopathology