By unraveling mechanisms by which hypertension translates into cardiovascular disease we hope to identify novel targets for therapy. Mechanical forces exerted by an elevated blood pressure are sensed and translated into biochemical signals by multiple mechanisms. In one project we have discovered that hypertension feeds into the NOTCH signaling pathway, heavily burdened by mutations in human stroke syndromes. This establishes a hitherto unknown mechanistic link between hypertension-driven stroke and syndromic stroke.

Caveolae are membrane organelles considered to play a mechanoprotective role. In another project we characterize mice that lack critical building blocks for caveolae with a view to understand a group of diseases referred to as caveolinopathies. In recent work, we identified what appears to be a critical genetic on-off switch for formation of caveolae: myocardin family coactivators. Current efforts focus on the details of this genetic control mechanism.

One of the most mechanoresponsive genes in the genome is thrombospondin-4 (Thbs4). Thbs4 encodes a matrix protein that also functions as an upstream activator of one arm of the unfolded protein response. We have discovered that mutant mice lacking Thbs4 develop maladaptive remodeling of the heart in Angiotensin II-driven hypertension. They are also strikingly susceptible to aneurysm development. We now try to understand the mechanistic basis of these phenotypes.

De krafter som ett förhöjt blodtryck utövar på hjärta och blodkärl är skadliga och accelererar åderförkalkning, aneurysmutveckling och njurskada. I gruppen cellulär bimekanik har vi som övergripande målsättning att förstå de molekylära mekanismer som aktiveras av mekaniska krafter. Arbetet bedrivs förutsättningslöst. Vi använder screeningmetoder för att identifiera gener som är mekanokänsliga. Sedan går vi vidare och undersöker det mekaniska svaret efter att dessa gener inaktiverats. Vi hoppas på så sätt kunna belysa viktiga sjukdomsprocesser och identifiera nya principer för terapi som kan komplettera traditionell blodtryckssänkande behandling.